JP2020109131A - Crystal of cyclic phosphonic acid sodium salt and method for manufacturing the same - Google Patents

Abstract

To provide crystals of cyclic phosphonic acid sodium salt (2ccPA) having high purity and excellent storage stability and a method for producing the crystals.SOLUTION: The present invention provides crystals of cyclic phosphonic acid sodium salt (2ccPA) represented by formula (1).SELECTED DRAWING: None

Description

The present invention relates to crystals of cyclic phosphonic acid sodium salt and a method for producing the same.

Formula (1) represented by cyclic phosphonate sodium salt (9-octadecenoic acid (9Z) - (-1,2-2-hydroxy-2-oxo-2 [lambda] ⁵ oxaphospholane-4-yl) methyl ester Sodium salt) is a compound generally referred to as 2ccPA.

This 2 ccPA is known to have a strong analgesic effect (Patent Document 1), an anti-cancer agent by suppressing the invasion of cancer cells (Patent Document 2), and a therapeutic agent for osteoarthritis by promoting hyaluronic acid production ( It is also expected as Patent Document 3).

Conventionally, 2 ccPA has been produced by the production method represented by the following reaction formula-1 (Patent Document 2, Patent Document 4, Non-Patent Document 1 and Non-Patent Document 2).

Specifically, first, the iodine compound (5a) obtained by the production method described in Non-Patent Document 2 is reacted with trimethyl phosphite to obtain dimethyl phosphonate (6a). Then, the compound (6a) is reacted with p-toluenesulfonic acid (p-TsOH) to obtain the compound (8a). 2 ccPA has been produced by introducing oleic acid into the compound (8a) to form the compound (9a), demethylating it, and further converting it into a sodium salt.

However, in the above production method, the reaction conditions in each step have not been optimized, and since it is necessary to perform purification by silica gel column chromatography in each step, the total yield of 2ccPA after the above 5 steps is When calculated from the yield described in the literature, the yield was low at 18.7%, which was not suitable for large-scale synthesis. Further, since bromotrimethylsilane (TMSBr) is used in the demethylation step, there is a risk that the reaction system becomes strongly acidic due to byproduct hydrogen bromide and the product is decomposed. In fact, the demethylation step had a low yield of 38%.

Furthermore, in the final step, the compound (10a) is converted to a sodium salt with an aqueous solution of sodium hydroxide to induce 2ccPA. However, since the compound (10a) is lyophilized without any purification, it is strongly added to the solid of 2ccPA. There is a possibility that basic sodium hydroxide may be mixed in, the decomposition of 2ccPA by sodium hydroxide cannot be avoided, and there is a problem in storage stability.

Therefore, it is desired to develop a method for producing a 2ccPA crystal, which is simpler, has a higher yield, a higher purity, and is excellent in storage stability as compared with conventionally known methods.

Japanese Patent No. 5077893 JP 2004-10582 A International Publication No. 2013/069404 International Publication No. 03/104246

Biochimica et Biophysica Acta, 2007, 1771, p.103-112. Tetrahedoron, 1991, Vol. 47, No. 6, p.1001-1012

An object of the present invention is to provide a 2ccPA crystal having high purity and excellent storage stability.

Another object of the present invention is to provide a method for producing crystals of 2ccPA simply and in high yield.

The present inventors have conducted extensive research to solve the above problems. As a result, a cyclic phosphonate, which is a precursor of 2ccPA, can be produced in high yield by a single purification of silica gel column chromatography, and further, the cyclic phosphonate can be converted into 2ccPA without using a strong acid or a strong base. I succeeded in inducing.

Furthermore, the present inventors have found that the crystals of 2ccPA thus obtained have excellent storage stability and can solve this problem. The present invention has been completed based on such findings.

That is, the present invention provides a 2ccPA crystal and a method for producing the same described below.
Item 1.
Formula (1)

A crystal of cyclic phosphonic acid sodium salt (2 ccPA) represented by:
Item 2.
Item 2. The crystal according to Item 1, which has a characteristic peak at a position of 15° to 17° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum.
Item 3.
Item 3. The crystal according to Item 1 or 2, which has a characteristic peak at a position of 9° to 10° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum.
Item 4.
Item 4. The crystal according to any one of Items 1 to 3, which has a characteristic peak at a position of 3° to 5° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum.
Item 5.
Item 5. The crystal according to Item 4, which has a characteristic peak at a position of 4.7° to 5.0° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum.
Item 6.
Item 5. The crystal according to Item 4, which has a characteristic peak at a position of 4.4° to 4.6° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum.
Item 7.
Item 5. The crystal according to Item 4, which has a characteristic peak at a position of 4.1° to 4.3° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum.
Item 8.
Item 5. The crystal according to Item 4, which has a characteristic peak at a position of 3.7° to 3.9° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum.
Item 9.
Item 9. The crystal according to any one of Items 1 to 8, which has a melting point of 187 to 190°C.
Item 10.
Item 10. A method for producing the crystal according to any one of Items 1 to 9,
Step (H): General formula (9)

(In the formula, R ¹ represents an alkyl group, an arylalkyl group or an aryl group.)
The step of reacting a cyclic phosphonate ester represented by the formula with sodium halide in an organic solvent to obtain 2 ccPA, and step (I): the solution containing 2 ccPA obtained in step (H) is depressurized. A production method, which comprises the step of precipitating crystals by concentrating the solution below or by cooling the solution containing 2 ccPA obtained in step (H).
Item 11.
Item 10. A method for producing a crystal according to Item 10, further comprising:
Step (J): a step of dissolving the crystal obtained in step (I) in water and/or an organic solvent to obtain a solution, and step (K): adding a poor solvent to the solution obtained in step (J) A method of manufacturing, comprising the step of recrystallizing by adding.
Item 12.
A crystal of cyclic phosphonic acid sodium salt (2 ccPA) obtained by the production method according to claim 10.
Item 13.
Formula (1)

A method for producing crystals of cyclic phosphonic acid sodium salt (2ccPA) represented by:
Step (H): General formula (9)

(In the formula, R ¹ represents an alkyl group, an arylalkyl group or an aryl group.)
The manufacturing method containing the process of making the cyclic phosphonate represented by and the sodium halide react in an organic solvent.
Item 14.
General formula (9)

(In the formula, R ¹ represents an alkyl group, an arylalkyl group or an aryl group.)
A method for producing a cyclic phosphonate represented by:
Step (G): General formula (8)

(In the formula, R ¹ is the same as the above.)
The manufacturing method including the process of making the compound represented by and the oleic acid compound react.
Item 15.
General formula (8)

(In the formula, R ¹ represents an alkyl group, an arylalkyl group or an aryl group.)
A method for producing a compound represented by:
Process (F): General formula (7)

(In the formula, two R ^{1 s} are the same or different and each represents an alkyl group, an arylalkyl group or an aryl group.)
The manufacturing method including the process of making a base act on the compound represented by.
Item 16.
General formula (7)

(In the formula, two R ^{1 s} are the same or different and each represents an alkyl group, an arylalkyl group or an aryl group.)
A method for producing a compound represented by:
Process (E): General formula (6)

(In the formula, R ¹ is the same as the above. Two R ² are the same or different and each represents an alkyl group, a cycloalkyl group or an aryl group.)
The manufacturing method including the process of making an acid act on the compound represented by.
Item 17.
General formula (6)

(In the formula, two R ¹ are the same or different and represent an alkyl group, an arylalkyl group or an aryl group. Two R ² are the same or different and represent an alkyl group, a cycloalkyl group or an aryl group. )
A method for producing a compound represented by:
Process (D): General formula (5)

(In the formula, R ² is the same as the above. X represents a halogen atom.)
The manufacturing method containing the process of making the compound represented by and the phosphite diester react.
Item 18.
General formula (5)

(In the formula, two R ² are the same or different and each represents an alkyl group, a cycloalkyl group or an aryl group. X represents a halogen atom.)
A method for producing a halogen compound represented by
Step (C): General formula (4)

(In the formula, R ² is the same as the above. R ³ is an optionally substituted alkyl group or an optionally substituted aryl group.)
A method for producing, comprising a step of reacting the compound represented by with an alkali metal halide and/or an alkaline earth metal halide in the presence of a base.
Item 19.
General formula (4)

(In the formula, two R ² are the same or different and each represents an alkyl group, a cycloalkyl group or an aryl group. R ³ represents an optionally substituted alkyl group or an optionally substituted aryl group. .)
A method for producing a compound represented by:
Step (B): General formula (3)

(In the formula, R ² is the same as the above.)
The manufacturing method containing the process of making the compound represented by and the sulfonyl halide compound react. Item 20.
General formula (5)

(In the formula, two R ² are the same or different and each represents an alkyl group, a cycloalkyl group or an aryl group. X represents a halogen atom.)
A method for producing a compound represented by:
Step (B'): General formula (3)

(In the formula, R ² is the same as the above.)
The manufacturing method including the process of making the compound represented by and the halogenating agent react.
Item 21.
Item 10. The method for producing a crystal according to Item 10 or 13, further comprising the step according to any one of Items 14 to 20.

The crystal of 2ccPA of the present invention is excellent in storage stability and hardly decomposes even if the crystal is stored for a long period of time.

By following the production method of the present invention, highly pure 2ccPA crystals can be produced in high yield by a simple means.

Specifically, the production method of the present invention includes a novel production method, and in particular, the present invention is a cyclic phosphonic acid which is a precursor of 2ccPA without isolation and purification in each step (telescoping method). Esters can be produced.

Further, the production method of the present invention can easily provide a 2ccPA crystal from a cyclic phosphonate ester, which can easily reduce the risk of deterioration in purity without using a strong acid or a strong base, and has excellent stability.

2 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 1. FIG. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 2. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 3. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 4. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 5. FIG. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 6. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 7. FIG. 9 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 8. FIG. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 9. FIG. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 10. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 11. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 12. 4 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 13. FIG. 4 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 14. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 15. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 16. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 17. 20 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 18. 20 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 19. FIG. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 20. 2 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 21. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 22. 9 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 23. FIG. 9 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 24. FIG. 9 is an X-ray powder diffraction spectrum of the crystal of 2ccPA obtained in Example 25. 3 is an X-ray powder diffraction spectrum of the 2ccPA crystal obtained in Example 26. It is a graph which shows the result of a stability test.

The novel crystal of 2ccPA of the present invention and the method for producing the same will be described in detail below.

In this specification, the expression "comprising" includes the terms "comprising", "consisting essentially of" and "consisting solely of".

1. Crystal of cyclic phosphonic acid sodium salt (2ccPA) The crystal of 2ccPA of the present invention is a cyclic phosphonic acid sodium salt (9-octadecenoic acid (9Z)-(2-hydroxy-2-oxo-) represented by the following formula (1). 2 [lambda] ^{5-1,2-oxaphospholane-4-yl)} sodium salt of methyl ester, IUPAC name: 4 - [(Z) - Okutadekku 9- enoyl oxymethyl] -2-oxo -1, 2-lambda ⁵ -oxaphospholane-2-olate sodium salt).

The crystal of 2 ccPA is, for example, an X-ray powder diffraction spectrum obtained by copper radiation of λ=1.54059Å through a monochromator when measured using RINT-2000 Ultima IV (trade name) manufactured by Rigaku Corporation. Has a characteristic peak at the following lattice spacing (d).

The 2 ccPA crystal has a diffraction angle represented by 2θ in a crystal X-ray powder diffraction spectrum,
A characteristic peak at a position of about 15° to 17° (hereinafter referred to as “peak A”),
A characteristic peak at about 9° to 10° (hereinafter referred to as “peak B”) or at least one characteristic peak at about 3° to 5° (hereinafter referred to as “peak C to F”). ) Is included.

The peaks C to F further include the following peaks C, D, E and/or F.
A characteristic peak at a position of about 4.7° to 5.0° (hereinafter referred to as "peak C")
A characteristic peak at a position of approximately 4.4° to 4.6° (hereinafter referred to as “peak D”)
A characteristic peak at a position of about 4.1° to 4.3° (hereinafter referred to as "peak E")
A characteristic peak at a position of about 3.7° to 3.9° (hereinafter referred to as "peak F")
The peak C is
It includes characteristic peaks at positions of about 4.7° to 4.9° and/or at positions of about 4.9° to 5.0°.

The 2 ccPA crystal in the present invention has a shape in which scale-like crystals are stacked.

The melting point of the 2ccPA crystal in the present invention is in the range of 187°C to 190°C. The melting point is measured using a melting point measuring device B-545 manufactured by Büch.

The IR spectrum of the 2 ccPA crystal in the present invention is measured using an IR measuring device Spectrum One B manufactured by Perkin Elmer.

The purity of the 2ccPA crystal in the present invention is measured by high performance liquid chromatography (HPLC) using a reversed phase silica gel column. Generally, the purity is 98% or higher.

The 2ccPA crystal of the present invention has excellent storage stability. Even if the 2 ccPA crystals are sealed and stored at −20° C. and 35° C. for 3 months, the purity is hardly lowered and the decomposition of 2 ccPA hardly occurs.

2. Method for Producing Crystal of 2ccPA The method for producing a crystal of 2ccPA of the present invention is characterized by including the following step (H) and step (I).

Step (H): General formula (9)

(In the formula, R ¹ is the same as the above.)
A step of reacting a cyclic phosphonate ester represented by the formula with sodium halide in an organic solvent to obtain 2 ccPA, and step (I): reducing the solution containing 2 ccPA obtained in step (H) under reduced pressure. The above-mentioned production method, which comprises a step of precipitating crystals by concentrating the solution below or by cooling the solution containing 2 ccPA obtained in the step (H).

Furthermore, the method for producing a 2ccPA crystal of the present invention may include the following step (J) and step (K) in addition to the above step (H) and step (I).

Step (J): a step of dissolving the crystals obtained in steps (H) and (I) in water and/or an organic solvent, and step (K): adding a poor solvent to the solution obtained in step (J) Recrystallization by adding

2-1. Process (H)
Step (H) is a step represented by the following reaction formula-2.

(In the formula, R ¹ is the same as the above.)
Specifically, the step (H) is a step of reacting a cyclic phosphonate represented by the general formula (9) with sodium halide in an organic solvent to obtain 2ccPA represented by the formula (1). And in the step (H), a solution containing 2 ccPA is obtained.

The cyclic phosphonate ester represented by the general formula (9) used in the step (H) is produced through the production steps described below.

In the cyclic phosphonate ester represented by the general formula (9), examples of the alkyl group represented by R ¹ include a linear or branched alkyl group having 1 to 10 carbon atoms, and specifically, methyl group. , Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl groups and the like. It is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group, an ethyl group, and an isopropyl group.

The alkyl group may have 1 to 5, preferably 1 to 3 substituents such as a halogen atom (eg, fluorine, chlorine, bromine), an alkoxy group having 1 to 6 carbon atoms, and a nitro group. Good.

Examples of the arylalkyl group represented by R ¹ include an arylalkyl group having 7 to 16 carbon atoms (the aryl portion has 6 to 10 carbon atoms, and the alkyl group portion has 1 to 6 carbon atoms), Specifically, benzyl; 1-phenylethyl, 2-phenylethyl; 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl; 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4-phenyl. Butyl; naphthylmethyl and the like. It is preferably an arylalkyl group having 7 to 11 carbon atoms, more preferably an arylalkyl group having 7 to 8 carbon atoms, and particularly preferably a benzyl group.

The aryl group constituting the above arylalkyl group represented by R ¹ is, for example, a halogen atom (for example, fluorine, chlorine, bromine, etc.), an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, nitro. It may have 1 to 5, preferably 1 to 3 substituents such as groups.

Examples of the aryl group represented by R ¹ include a monocyclic or bicyclic or more aryl group, and specific examples include a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, and the like. Of these, a phenyl group which may have a substituent is preferable. The aryl group is, for example, a halogen atom (for example, fluorine, chlorine, bromine, etc.), an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, 1 to 5 substituents such as a nitro group, Preferably, it may have 1 to 3.

As the sodium halide used in the step (H), known ones can be widely used, and examples thereof include sodium fluoride, sodium chloride, sodium bromide and sodium iodide. Among these, sodium iodide is preferable. The sodium halide may be used alone or in combination of two or more.

The amount of the sodium halide used is usually 1 to 5 mol, preferably 1 to 3 mol, and more preferably 1 to 1. 1 mol based on 1 mol of the compound represented by the general formula (9). It is 5 mol.

The organic solvent used in step (H) is not particularly limited as long as it does not adversely affect the reaction. Examples of the organic solvent used include ketone solvents (branched or linear ketones and cyclic ketones such as acetone, methyl ethyl ketone, methyl butyl ketone, methyl isobutyl ketone, DIBK (diisobutyl ketone), cyclohexanone), alcohol solvents (Eg, methanol, ethanol, etc.), ether solvent (diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.), aromatic hydrocarbon solvent (eg, benzene, toluene, xylene, etc.), fat Group or alicyclic hydrocarbon solvents (n-pentane, n-hexane, cyclohexane, petroleum ether, etc.), ester solvents (ethyl acetate, etc.), halogenated hydrocarbon solvents (methylene chloride, chloroform, 1,2- Dichloroethylene etc.) and the like. The organic solvent may be used alone or in combination of two or more. Among these organic solvents, ketone solvents are preferable, and acetone, methyl ethyl ketone and methyl isobutyl ketone are particularly preferable.

The amount of the organic solvent used can be appropriately selected from a wide range, and is generally 2 to 20 liters, preferably 2 to 5 liters, relative to 1 mol of the compound represented by the general formula (9). is there.

The step (H) may be performed in an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is usually 0 to 120°C, preferably 50 to 120°C, more preferably 70 to 120°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 1 to 24 hours.

After completion of the reaction, excess reagents (for example, sodium halide), unreacted raw material compounds and the like are removed from the resulting reaction mixture by a usual separation method such as concentration, crystallization and filtration to obtain the desired general formula. 2 ccPA represented by (1) can be taken out.

2-2. Process (I)
In step (I), crystals are precipitated by concentrating the solution containing 2ccPA obtained in step (H) under reduced pressure or cooling the solution containing 2ccPA obtained in step (H). It is the process of making.

The depressurization in step (I) is not particularly limited as long as it is a pressure at which crystals are precipitated, and is usually less than atmospheric pressure.

The cooling temperature in the step (I) is not particularly limited as long as it is a temperature for precipitating crystals, and is usually lower than the temperature of the solution after the reaction in the step (H), preferably 0 to 30° C., 10-25 degreeC is preferable.

The cooling time is not particularly limited and is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 1 to 2 hours.

The crystals obtained can then be used in step (J).

2-3. Process (J)
Step (J) is a step of dissolving the crystals obtained in steps (H) and (I) in water and/or an organic solvent to obtain a solution.

The water and/or organic solvent used in step (J) may be water and/or an organic solvent capable of dissolving the crystals obtained in step (I). Examples of the organic solvent include alcohol solvents, with methanol, ethanol, 1-propanol, isopropyl alcohol, and 1-butanol being particularly preferable.

The amount of water and/or the organic solvent used can be appropriately selected from a wide range, and for example, is generally 0.5 to 20 liters, preferably 0.5 to 2 liters, relative to 1 mol of 2 ccPA. ..

When a mixed solvent of water and an organic solvent is used, the mixing ratio thereof is not particularly limited, and the mixing ratio of water and the organic solvent is preferably 1:99 to 99:1, more preferably 30:70 to 70:30. preferable.

The temperature for dissolution is not particularly limited and is usually 0 to 100°C, preferably 10 to 80°C, and more preferably 20 to 60°C.

The time of the step (J) is not particularly limited and is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 1 to 2 hours.

2-4. Process (K)
Step (K) is a step of performing recrystallization by adding a poor solvent to the solution obtained in step (J).

The poor solvent used in the step (K) may be any solvent capable of precipitating crystals from the solution obtained in the step (J). Specifically, the poor solvent may be a poorer solvent than the solvent (good solvent) used in the step (J), and examples thereof include a ketone solvent (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), an ether solvent. (Diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.), aromatic hydrocarbon solvent (eg, benzene, toluene, xylene, etc.), aliphatic or alicyclic hydrocarbon solvent (n- Pentane, n-hexane, cyclohexane, petroleum ether, etc., ester solvents (methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, etc.), halogenated hydrocarbon solvents (methylene chloride, chloroform, 1,2-dichloroethylene, etc.) , An alcohol solvent having 3 or more carbon atoms (for example, 1-propanol), and the like.

Further, the solvent used in this step (K) may be a poorer solvent than the solvent (good solvent) used in the step (J). For example, when the solvent used in the step (K) is methanol, the poor solvent may be: An alcohol solvent having 3 or more carbon atoms (for example, 1-propanol) can be used. The organic solvent may be used alone or in combination of two or more. Among these organic solvents, ketone solvents are preferable, and acetone, methyl ethyl ketone and methyl isobutyl ketone are particularly preferable.

The amount of the poor solvent used can be appropriately selected from a wide range and is, for example, generally 1 to 30 liters, preferably 2 to 5 liters, relative to 1 mol of 2 ccPA.

The temperature at which the poor solvent is added is usually -20°C to 30°C, preferably -10°C to 20°C, and more preferably 0°C to 20°C.

Crystals of cyclic phosphonic acid sodium salt (2 ccPA) obtained by the production method including the above step (H) and step (I) or obtained by the production method including the above steps (H) to (K) have a high It has the advantages of purity and excellent storage stability.

3. Method for producing cyclic phosphonate represented by general formula (9) The cyclic phosphonate represented by general formula (9) in the present invention can be produced through the steps shown in the following reaction formula-3.

(In the formula, R ¹ , R ² , R ³ , and X are the same as above.)
The steps (A) to (G) will be described in detail below.

3-1. Step (A): (Acetal protection step)
The step (A) is a step represented by the following reaction formula-4.

(In the formula, R ² is the same as the above.)
Specifically, in the step (A), 2-hydroxymethyl-1,3-propanediol represented by the above formula (2) is reacted with a ketone compound or an acetal compound in the presence of an acid to give a compound represented by the general formula: It is a step of producing the cyclic acetal compound represented by (3) (acetal protection step).

The ketone compound used in the step (A) is not particularly limited as long as it is an organic compound having a keto group. Examples of the ketone compound include a ketone compound represented by the following general formula (10).

(In the formula, R ² is the same as the above. Two R ² may combine with each other to form an alkylene group, and the alkylene group may further have a substituent.)
The acetal compound used in the step (A) is not particularly limited, and examples thereof include an acetal compound represented by the following general formula (11).

(In the formula, R ² is the same as the above. Two R ² may combine with each other to form an alkylene group, and the alkylene group may further have a substituent. Two R ⁴ Are the same or different and each represents an alkyl group.)
In the ketone compound represented by the general formula (10) or the acetal compound represented by the general formula (11), the alkyl group represented by R ² is, for example, a chain or branched alkyl group having 1 to 10 carbon atoms. And specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n. -Nonyl group etc. are mentioned. It is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group, an ethyl group, and an isopropyl group. The alkyl group has, for example, 1 to 5, preferably 1 to 3 substituents such as a halogen atom (eg, fluorine, chlorine, bromine, etc.), an aryl group (eg, phenyl group, naphthyl group, etc.) and a carboxyl group. You may have one.

In the ketone compound represented by the general formula (10) or the acetal compound represented by the general formula (11), the cycloalkyl group in the cycloalkyl group which may have a substituent represented by R ² is, for example, And a cycloalkyl group having 3 to 10 carbon atoms, and specific examples thereof include a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl group. A cycloalkyl group having 3 to 7 carbon atoms is preferable, a cycloalkyl group having 5 to 7 carbon atoms is more preferable, and a cyclohexyl group is particularly preferable. The cycloalkyl group is, for example, a halogen atom (eg, fluorine, chlorine, bromine, etc.), an alkyl group (alkyl group having 1 to 6 carbon atoms), an aryl group (eg, phenyl group, naphthyl group, etc.), a carboxyl group, etc. It may have 1 to 5, preferably 1 to 3 substituents.

In the ketone compound represented by the general formula (10) or the acetal compound represented by the general formula (11), the aryl group in the aryl group which may have a substituent represented by R ² is, for example, a single group. Examples thereof include a ring or an aryl group having two or more rings, and specific examples thereof include a phenyl group, a naphthyl group, an anthryl group, and a phenanthryl group. Of these, a phenyl group which may have a substituent is preferable. The aryl group has, for example, 1 to 5, preferably 1 to 3 substituents such as a halogen atom (for example, fluorine, chlorine, bromine, etc.), an alkyl group (alkyl group having 1 to 6 carbon atoms), a carboxyl group and the like. You may have one.

In the general formula (10) or (11), two R ^{2 s} may be bonded to each other to form an alkylene group, and the alkylene group may have a substituent. When two R ^{2 s} are bonded to each other to form an alkylene group, examples of the alkylene group include —(CH ₂ ) _q — (q is an integer of 1 to 6) and —(CH═CH) _r. - (r denotes 1, 2 or _{3), - CH = CH- (} CH 2) s - (s shows 1, 2 or 3), and the like.

The alkylene group may have a substituent, and examples of the substituent include an alkyl group (for example, an alkyl group having 1 to 6 carbon atoms), an aryl group (for example, a phenyl group, a naphthyl group), and an oxo group. A group (=O), a halogen atom (for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom) and the like can be mentioned. The divalent hydrocarbon group may have 1 to 5 substituents selected from the group consisting of these.

In the acetal compound represented by the general formula (11), examples of the alkyl group represented by R ⁴ include a linear or branched alkyl group having 1 to 10 carbon atoms, and specifically, methyl and ethyl. , N-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl group and the like. It is preferably an alkyl group having 1 to 6 carbon atoms, more preferably an alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group, an ethyl group, and an isopropyl group. The alkyl group has, for example, 1 to 5, preferably 1 to 3 substituents such as a halogen atom (eg, fluorine, chlorine, bromine, etc.), an aryl group (eg, phenyl group, naphthyl group, etc.) and a carboxyl group. You may have one.

Specific examples of the ketone compound used in the step (A) include acetone, 2-butanone (methyl ethyl ketone), 2-pentanone, 3-pentanone, 4-methyl-2-pentanone, methyl isopropyl ketone, methyl isobutyl ketone, 2-hexanone, 3-hexanone, 2-heptanone, 3-heptanone, 2-octanone, 3-octanone, 2-nonanone, 2-decanone, 4-decanone, 2-undecanone, 6-undecanone and the like having 3 to 20 carbon atoms. A chain aliphatic ketone compound having 6 to 20 carbon atoms such as 2-methylcyclohexanone, 3-methylcyclohexanone, 3-methylcyclopentanone and 4-acetyl-1-methylcyclohexene; acetophenone; -(4-chlorophenyl)-1-ethanone, 1-(2-chlorophenyl)-1-ethanone, 1-(4-fluorophenyl)-1-ethanone, 1-(2-fluorophenyl)-1-ethanone, 1 -(4-Methylphenyl)-1-ethanone, 1-(2-methylphenyl)-1-ethanone, 1-(4-nitrophenyl)-1-ethanone, 1-(4-tert-butylphenyl)-1 -Ethanone, 1-(4-methoxyphenyl)-1-ethanone, 1-(4-allyloxycarbonylphenyl)-1-ethanone, 1-phenyl-2-propanone, methyl 4-oxo-4-phenylbutanoate, Ethyl 4-oxo-4-phenylbutanoate, 1-phenyl-2-butanone, 4-phenyl-2-butanone, 2-phenylcyclopentanone, 2-phenylcycloheptanone, 9-acetylanthracene, 2-acetylbiphenyl Aromatic ketone compounds having 6 to 20 carbon atoms such as 4-acetylbiphenyl, 2-acetylnaphthalene, 2-acetylphenanthrene, 3-acetylphenanthrene, and 9-acetylphenanthrene; aralkylketone compounds such as 2-acetyl-5-norbornene Etc. can be mentioned.

Among these compounds, acetone, 2-pentanone, 3-pentanone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, cyclobutanone, cyclopentanone, cyclohexanone and the like can be mentioned. Particularly, acetone, methyl ethyl ketone, and methyl isobutyl ketone are preferable.

Specific examples of the acetal compound used in the present invention include 2,2-dimethoxypropane, 2,2-diethoxypropane, 2,2-dipropoxypropane, 2,2-dibutoxypropane, 1,1- Dimethoxycyclohexane, 1,1-dimethylcyclopentane, benzophenone dimethylacetal, 2,2-dimethyl-1,3-dioxolane, 4,4-dimethoxyheptane, 5,5-dimethoxynonane, 4,4-diethoxyheptane Examples include 5,5-diethoxynonane and the like. Particularly, 2,2-dimethoxypropane, 2,2-dipropoxypropane, 2,2-dibutoxypropane, and benzophenone dimethyl acetal are preferable.

Examples of the acid used in the step (A) include known inorganic acids and organic acids. Examples of the inorganic acid include hydrochloric acid and sulfuric acid. Examples of the organic acid include sulfonic acid compounds such as methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pyridine paratoluenesulfonate, and carboxylic acid compounds such as acetic acid. As the acid, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, pyridine paratoluenesulfonate, acetic acid and the like are particularly preferable. Here, when acetic acid is used, it can also serve as a solvent.

The amount of the acid used can be appropriately selected from a wide range, and is generally 0.01 with respect to 1 mol of 2-hydroxymethyl-1,3-propanediol represented by the above formula (2). To 500 mol, preferably 0.01 to 2 mol, and more preferably 0.01 to 1 mol.

Step (A) is carried out without solvent or in the presence of a solvent. When a solvent is used, the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent used include alcohol solvents (for example, methanol, ethanol, etc.), ether solvents (diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.), aromatic hydrocarbon solvents ( For example, benzene, toluene, xylene, etc.), aliphatic or alicyclic hydrocarbon solvent (n-pentane, n-hexane, cyclohexane, petroleum ether, etc.), ester solvent (ethyl acetate, etc.), halogenated hydrocarbon solvent Examples thereof include solvents (methylene chloride, chloroform, 1,2-dichloroethylene, etc.). The solvent may be used alone or in combination of two or more. Of these solvents, methanol, THF, 1,4-dioxane and toluene are preferable, and THF is particularly preferable.

The amount of the solvent used can be appropriately selected from a wide range and is, for example, generally 0 to 20 liters, preferably 0 to 5 liters, relative to 1 mol of the compound represented by the general formula (2). ..

Step (A) can be performed under an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally 0 to 100°C, preferably 10 to 80°C, more preferably 20 to 80°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 1 to 10 hours.

After completion of the reaction, excess reagents (ketone compounds, etc.), unreacted raw material compounds, etc. are removed from the resulting reaction mixture by usual separation methods such as liquid separation, distillation, column purification, etc. The cyclic acetal compound represented by 3) can be taken out. Further, after the completion of the reaction, only concentration may be performed and the mixture after the reaction may be directly used in the step (B) without performing the purification and isolation steps (telescoping synthesis).

3-2. Step (B): (Sulfonylation Step)
Step (B) is a step represented by the following reaction formula-5.

(In the formula, R ² and R ³ are the same as above.)
Step (B) is a step (sulfonylation step) of reacting the compound represented by the general formula (3) with a sulfonyl halide compound to obtain the compound represented by the general formula (4).

In the step (B), for example, by reacting the alcohol compound represented by the general formula (3) with a sulfonyl halide compound in the presence of a base in an organic solvent, the compound represented by the general formula (4) is represented. And a step of obtaining a sulfonate compound. For the reaction using, for example, mesyl chloride as a sulfonyl compound, the method described in Non-Patent Document 2 can be referred to.

Examples of the sulfonyl halide compound used in the step (B) include alkylsulfonyl chlorides such as methylsulfonyl chloride, methylsulfonyl bromide and methylsulfonyl iodide; arylsulfonyl chlorides such as phenylsulfonyl chloride and tosyl chloride.

The amount of the sulfonyl halide compound used can be appropriately selected from a wide range, and is generally 1 to 500 mol, preferably 1 to 10 mol with respect to 1 mol of the methanol compound represented by the above formula (3). Mol, more preferably 1 to 2 mol.

Step (B) is carried out without solvent or in the presence of a solvent. When a solvent is used, the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent used include alcohol solvents (for example, methanol, ethanol, etc.), ether solvents (diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, etc.), aromatic hydrocarbon solvents ( For example, benzene, toluene, xylene, etc.), aliphatic or alicyclic hydrocarbon solvent (n-pentane, n-hexane, cyclohexane, petroleum ether, etc.), ester solvent (ethyl acetate, etc.), halogenated hydrocarbon solvent Examples of the solvent include methylene chloride (MDC, DCM), chloroform, 1,2-dichloroethylene and the like. The solvent may be used alone or in combination of two or more. Of these solvents, THF, 1,4-dioxane, toluene and methylene chloride are preferable, and methylene chloride is particularly preferable.

The amount of the solvent used can be appropriately selected from a wide range and is, for example, generally 0 to 20 liters, preferably 1 to 5 liters, relative to 1 mol of the compound represented by the general formula (2). ..

The step (B) can be performed under an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally -40 to 100°C, preferably -30 to 80°C, more preferably -20 to 20°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 1 to 4 hours.

After completion of the reaction, excess reagents (sulfonyl halide compound, etc.), unreacted raw material compounds, etc. are removed from the resulting reaction mixture by usual separation methods such as liquid separation, concentration, column purification, etc. The cyclic acetal compound represented by (4) can be taken out. Further, after completion of the reaction, only liquid separation and concentration are performed, and the mixture after the reaction can be used as it is in the step (C) without performing the purification and isolation steps (telescoping synthesis).

3-3. Process (C): (halogenation process)
Step (C) is a step represented by the following reaction formula-6.

(In the formula, R ² , R ³ and X are the same as above.)
Specifically, in the step (C), the compound represented by the general formula (4) is reacted with an alkali metal halide and/or an alkali metal earth halide in the presence of a base to give a compound represented by the general formula ( This is a step (halogenation step) of obtaining the compound represented by 5).

The alkali metal halide used in the step (C) is not particularly limited, and examples thereof include lithium halide (eg, lithium fluoride, lithium chloride, lithium bromide, lithium iodide, etc.) and sodium halide (eg, fluorine). Sodium iodide, sodium chloride, sodium bromide, sodium iodide, etc., potassium halide (eg, potassium fluoride, potassium chloride, potassium bromide, potassium iodide, etc.), cesium halide (eg, cesium fluoride, chloride) Cesium, cesium bromide, cesium iodide, etc.) and the like. Among these, sodium iodide is preferable. The alkali metal halides can be used alone or in combination of two or more.

The alkali metal earth halide used in the step (C) is not particularly limited, and examples thereof include magnesium halide (eg, magnesium fluoride, magnesium chloride, magnesium bromide, magnesium iodide, etc.) and calcium halide (eg, , Calcium fluoride, calcium chloride, calcium bromide, calcium iodide, etc., strontium halide (eg, strontium fluoride, strontium chloride, strontium bromide, strontium iodide, etc.), barium halide (eg, barium fluoride) , Barium chloride, barium bromide, barium iodide, etc.) and the like. The alkali metal earth halides may be used alone or in combination of two or more.

The amount of alkali metal halide and/or alkali metal earth halide used is usually 1 mol or more, preferably 1 to 10 mol, and more preferably 1 mol with respect to 1 mol of the compound represented by the general formula (4). It is 1 to 3 mol.

Examples of the base used in step (C) include organic bases and inorganic bases.

Examples of the organic base include organic amines having 1 to 3 and preferably 3 alkyl groups having 1 to 4 carbon atoms such as trimethylamine, triethylamine, tributylamine and diisopropylethylamine. In particular, triethylamine is preferable.

Specific examples of the inorganic base include alkali metal and alkaline earth metal carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate and calcium carbonate. Particularly, sodium hydrogen carbonate is preferable.

The amount of the base used may be a catalytic amount, and is usually 0.01 mol or more, preferably 0.01 to 1 mol, and more preferably 0, with respect to the sulfonate compound represented by the general formula (4). 0.05 to 0.5 mol.

In the step (C), the decomposition reaction can be prevented by adding a catalytic amount of the base, and the halogen compound represented by the general formula (5) can be obtained in high yield.

Step (C) is carried out without solvent or in the presence of a solvent. When a solvent is used, the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent used include ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), alcohol solvents (eg, methanol, ethanol, etc.), ether solvents (diethyl ether, diisopropyl ether, tetrahydrofuran (THF)). , 1,4-dioxane, etc.), aromatic hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), aliphatic or alicyclic hydrocarbon solvents (n-pentane, n-hexane, cyclohexane, petroleum ether, etc.) ), ester solvents (ethyl acetate, etc.), halogenated hydrocarbon solvents (methylene chloride, chloroform, 1,2-dichloroethylene, etc.) and the like. The solvent may be used alone or in combination of two or more. Of these solvents, acetone, methyl ethyl ketone and methyl isobutyl ketone are particularly preferable.

The amount of the solvent used can be appropriately selected from a wide range and is, for example, generally 0 to 20 liters, preferably 1 to 5 liters, relative to 1 mol of the compound represented by the general formula (4). ..

Step (C) can be performed in an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally 0 to 120°C, preferably 10 to 100°C, more preferably 55 to 80°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 1 to 18 hours.

This reaction is a novel reaction using a base in the halogenation reaction.

After completion of the reaction, excess reagents (alkali metal halide, alkali metal earth, base, etc.), unreacted raw material compounds, etc. are separated from the resulting reaction mixture by conventional separation methods such as liquid separation, concentration, column purification, etc. By removing, the desired compound represented by the general formula (5) can be taken out. Further, after the completion of the reaction, the mixture after the reaction can be used as it is in the step (D) without performing the purification and isolation steps (telescoping synthesis).

3-4. Step (B'): (Alternative halogenation step)
Step (B′) is a step represented by the following reaction formula-7.

(In the formula, R ² and X are the same as above.)
Specifically, the step (B') is a step of reacting the cyclic acetal compound represented by the general formula (3) with a halogenating agent.

The halogenating agent used in step (B') is not particularly limited. For example, in the case of chlorination, chlorine, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, triphenylphosphine-carbon tetrachloride, triphenylphosphine-N-chlorosuccinimide and the like can be mentioned. In the case of bromination, bromine, hydrobromic acid, phosphorus tribromide, triphenylphosphine-bromine, triphenylphosphine-N-bromosuccinimide, triphenylphosphine-carbon tetrabromide, thionyl bromide and the like can be mentioned. In the case of iodination, iodine, triphenylphosphine-iodine, triphenylphosphine-N-iodosuccinimide and the like can be mentioned. Among these, triphenylphosphine-iodine or triphenylphosphine-carbon tetrabromide is preferable.

The amount of the halogenating agent used is usually 1 to 500 mol, preferably 1 to 10 mol, and more preferably 1 to 2 mol with respect to 1 mol of the alcohol compound represented by the general formula (3). ..

Step (B') can be reacted in the presence of imidazole to scavenge the acid generated in the reaction.

The amount of imidazole used is, for example, usually 1 to 500 mol, preferably 1 to 10 mol, and more preferably 1 to 2 mol, based on the cyclic acetal compound represented by the general formula (3). ..

Step (B') is carried out without solvent or in the presence of a solvent. When a solvent is used, the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent used include ketone solvents (eg, acetone, methyl ethyl ketone, methyl isobutyl ketone, etc.), alcohol solvents (eg, methanol, ethanol, etc.), ether solvents (diethyl ether, diisopropyl ether, cyclopentyl methyl ether ( CPME), tetrahydrofuran (THF), 1,4-dioxane, etc.), aromatic hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), aliphatic or alicyclic hydrocarbon solvents (n-pentane, n-). Hexane, cyclohexane, petroleum ether, etc., ester solvents (ethyl acetate, etc.), halogenated hydrocarbon solvents (methylene chloride, chloroform, 1,2-dichloroethylene, etc.) and the like. The solvent may be used alone or in combination of two or more. Of these solvents, acetone, methyl ethyl ketone and methyl isobutyl ketone are particularly preferable.

The amount of the solvent used can be appropriately selected from a wide range and is, for example, generally 0 to 20 liters, preferably 1 to 5 liters, relative to 1 mol of the compound represented by the general formula (4). ..

The step (B') can be performed under an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally 0 to 100°C, preferably 0 to 40°C, more preferably 0 to 20°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 1 to 5 hours.

After completion of the reaction, excess reagents (halogenating agent, etc.), unreacted raw material compounds, etc. are removed from the resulting reaction mixture by usual separation methods such as liquid separation, concentration, column purification, etc. The compound represented by (5) can be taken out. Further, after the completion of the reaction, the mixture after the reaction can be used as it is in the step (D) without performing the purification and isolation steps (telescoping synthesis).

3-5. Step (D): (phosphonic acid diesterification step)
Step (D) is a step represented by the following reaction formula-8.

(In the formula, R ¹ , R ² and X are the same as above.)
Specifically, the step (D) is a step of reacting the compound represented by the general formula (5) with a phosphite diester in the presence of a base to obtain the compound represented by the general formula (6). (Phosphonic acid diesterification step).

Examples of the phosphite diester used in the step (D) include the following general formula (12).

(In the formula, R ¹ is the same as the above.)
The compound represented by can be mentioned.

In the phosphite diester represented by the general formula (12), the alkyl group, the arylalkyl group or the aryl group represented by R ¹ is R mentioned in the cyclic phosphonate ester represented by the general formula (9). It is the same as the alkyl group, arylalkyl group or aryl group represented by ¹ .

Specific examples of the phosphite diester include, for example, dimethyl phosphite, diethyl phosphite, dipropyl phosphite, dibutyl phosphite, diisopropyl phosphite, and dialkyl phosphite such as methylethyl phosphite; Diaryl phosphite such as dibenzyl phosphite and di(phenylethyl) phosphite; diphenyl phosphite such as diphenyl phosphite and ditolyl phosphite; and the like, preferably dimethyl phosphite and phosphorus Diethyl acid, dibenzyl phosphite, and diphenyl phosphite.

The amount of the phosphite diester used is not particularly limited, and is preferably in the range of 1 to 10 equivalents, particularly preferably 2 to 2.5 equivalents, relative to the halogen compound represented by the general formula (5). ..

The solvent used in step (D) is not particularly limited as long as it is an organic solvent, and for example, an aprotic polar solvent can be used. Examples of the aprotic polar solvent include N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone and the like. Amide solvent, dimethylsulfoxide (DMSO), hexamethylphosphoric triamide (HMPA), acetonitrile (AN), acetone, THF and the like. Particularly, DMF, DMAc and acetonitrile are preferable. These solvents can be used alone or in combination of two or more.

The amount of the solvent used can be appropriately selected from a wide range and is, for example, generally 0 to 20 liters, preferably 1 to 5 liters, relative to 1 mol of the compound represented by the general formula (5). ..

Examples of the base used in step (D) include organic bases and inorganic bases.

Examples of the organic base include organic amines having 1 to 3 and preferably 3 alkyl groups having 1 to 4 carbon atoms such as trimethylamine, triethylamine, tributylamine and diisopropylethylamine. In particular, triethylamine is preferable.

Specific examples of the inorganic base include alkali metal and alkaline earth metal carbonates such as sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, rubidium carbonate, calcium carbonate, and cesium carbonate. .. Particularly, cesium carbonate and rubidium carbonate are preferable.

The amount of the base used is not particularly limited, but is preferably in the range of 1 to 10 equivalents, and particularly preferably 2 to 2.5 equivalents with respect to the compound represented by the above formula (5).

Step (D) can be performed in an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally 0 to 120°C, preferably 20 to 80°C, more preferably 40 to 50°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 5 to 8 hours.

After completion of the reaction, excess reagents (phosphorous acid diester, base, etc.), unreacted raw material compounds, etc. are removed from the resulting reaction mixture by usual separation methods such as concentration, filtration, column purification, etc. The compound represented by the general formula (6) can be taken out. Alternatively, after the reaction, only concentration and filtration may be performed, and the mixture after the reaction may be directly used in the step (E) without performing the purification and isolation steps (telescoping synthesis).

3-6. Step (E): (ring opening step)
Step (E) is a step represented by the following reaction formula-9.

(In the formula, R ¹ and R ² are the same as above.)
Specifically, the step (E) is a step (ring-opening step) of reacting the compound represented by the general formula (6) with an acid to obtain the compound represented by the general formula (7).

As the acid, any of known organic acids and inorganic acids can be used. Examples of the organic acid include sulfonic acids such as p-toluenesulfonic acid (p-TsOH), pyridinium p-toluenesulfonate (PPTS) and camphorsulfonic acid (CSA), formic acid, acetic acid, propionic acid, butyric acid, and triacetic acid. Examples thereof include lower fatty acids having 1 to 4 carbon atoms such as fluoroacetic acid (TFA). Particularly, p-TsOH and CSA are preferable.

Specific examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid and the like. Hydrochloric acid is particularly preferable.

The amount of the acid used is not particularly limited and is preferably in the range of 0.01 to 0.2 mol, particularly 0.01 to 0.1 mol, relative to 1 mol of the compound represented by the formula (6). Is preferred.

Step (E) is carried out without solvent or in the presence of a solvent. When a solvent is used, the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent used include water, alcohol solvents (for example, lower alcohols having 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, and n-butanol), ether solvents (diethyl ether, diisopropyl ether). , Tetrahydrofuran (THF), 1,4-dioxane, etc.), aromatic hydrocarbon solvents (eg, benzene, toluene, xylene, etc.), aliphatic or alicyclic hydrocarbon solvents (n-pentane, n-hexane, etc.). Examples thereof include cyclohexane, petroleum ether, etc., ester solvents (ethyl acetate, etc.), halogenated hydrocarbon solvents (methylene chloride, chloroform, 1,2-dichloroethylene, etc.). The solvent may be used alone or in combination of two or more. Of these solvents, methanol, THF, 1,4-dioxane and toluene are preferable, and methanol is particularly preferable.

The amount of the solvent used can be appropriately selected from a wide range and is, for example, generally 0 to 20 liters, preferably 1 to 5 liters, relative to 1 mol of the compound represented by the general formula (6). ..

The step (E) can be performed in an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally 0 to 120°C, preferably 0 to 80°C, more preferably 0 to 20°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 3 to 12 hours.

After the completion of the reaction, excess reagents (such as acid) and unreacted starting compounds are removed from the resulting reaction mixture by a usual separation method such as concentration and column purification, and the desired general formula (7) is obtained. The compound can be removed. Further, after the completion of the reaction, only concentration is performed, and the mixture after the reaction can be used as it is in the step (F) without performing the purification and isolation steps (telescoping synthesis).

3-7. Process (F): (cyclization process)
Step (F) is a step represented by the following reaction formula-10.

(In the formula, R ¹ is the same as the above.)
Specifically, the step (F) is a step (cyclization step) of reacting the compound represented by the general formula (7) with a base to obtain the compound of the general formula (8).

As the base used in the step (F), both known organic bases and inorganic bases can be used. For example, as the organic base, a tertiary organic amine such as diazabicycloundecene (DBU), diazabicyclononene (DBN), trimethylamine, triethylamine (TEA), tributylamine, diisopropylethylamine (DIPEA); sodium methoxide Examples thereof include metal alkoxides such as (NaOMe), sodium ethoxide (NaOEt), potassium t-butoxy (t-BuOK), and sodium t-butoxy (t-BuONa).

Examples of the inorganic base include alkali metal carbonates such as cesium carbonate (Cs ₂ CO ₃ ) and rubidium carbonate (Rb ₂ CO ₃ ); alkali metal hydrides such as sodium hydride (NaH).

The preferred base, DBU, a DBN, TEA, DIPEA, NaOMe, NaOEt, t-BuOK, t-BuONa, Cs 2 CO 3 and NaH, more preferably DBU and DBN.

The amount of the base used is not particularly limited, and is preferably in the range of 0.1 to 2 mol, particularly 0.1 to 1 mol, relative to 1 mol of the compound represented by the general formula (7). Is preferred.

Step (F) is carried out without solvent or in the presence of a solvent. When a solvent is used, the solvent is not particularly limited as long as it does not adversely affect the reaction. Examples of the solvent used include water, alcohol solvents (for example, lower alcohols having 1 to 4 carbon atoms such as methanol, ethanol, n-propanol, isopropanol, n-butanol); ether solvents (diethyl ether, diisopropyl ether). (IPA), tetrahydrofuran (THF), 1,4-dioxane, etc.; aromatic hydrocarbon solvent (eg, benzene, toluene, xylene, etc.); aliphatic or alicyclic hydrocarbon solvent (n-pentane, n) -Hexane, cyclohexane, petroleum ether, etc.; ester solvents (ethyl acetate, etc.); halogenated hydrocarbon solvents (methylene chloride, chloroform, 1,2-dichloroethylene, etc.); amide solvents (for example, N,N-dimethyl) Formamide (DMF), N,N-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), 1,3-dimethyl-2-imidazolidinone, etc.); dimethyl sulfoxide (DMSO); hexamethylphosphoric triamide (HMPA) ); Acetonitrile (AN); A solvent such as acetone can be used alone or in combination of two or more. Of these solvents, DMF, DMAc, AN, acetone, methanol, IPA and butanol are preferable, and DMF and DMAc are particularly preferable.

The amount of the solvent used can be appropriately selected from a wide range and is, for example, generally 0 to 20 liters, preferably 1 to 5 liters, relative to 1 mol of the compound represented by the general formula (7). ..

Further, in the reaction of the step (E), a quenching agent can be used to stop the reaction. A known quenching agent can be used as the quenching agent, and for example, an organic acid can be used. Examples of the organic acid include sulfonic acids such as p-TsOH and CSA, and fatty acids having 1 to 4 carbon atoms such as formic acid, acetic acid, propionic acid, butyric acid, and trifluoroacetic acid. Particularly, p-TsOH and CSA are preferable.

The amount of the quenching agent used is preferably the same molar amount as the organic base added in the reaction.

The step (E) can be performed in an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally 0 to 60°C, preferably 0 to 40°C, more preferably 15 to 25°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 2 to 7 hours.

After completion of the reaction, excess reagents (base, etc.), unreacted raw material compounds, etc. are removed from the resulting reaction mixture by a usual separation method such as concentration and column purification, and the desired general formula (8) is obtained. The compound can be removed. Further, after the completion of the reaction, only concentration is performed, and the mixture after the reaction can be used as it is in the step (G) without performing purification and isolation steps (telescoping synthesis).

3-8. Step (G) (esterification step)
Step (G) is a step represented by the following reaction formula-11.

(In the formula, R ¹ is the same as the above.)
Specifically, the step (G) is a step (esterification step) of reacting a cyclic phosphonic acid compound represented by the general formula (8) with an oleic acid compound to obtain a compound of the general formula (9). A known esterification reaction can be applied as appropriate.

Examples of the oleic acid compound include oleic acid and oleic acid derivatives such as oleic acid halide, oleic acid anhydride, and oleic acid ester. These oleic acid compounds may be used alone or in combination of two or more.

Examples of the halide in the oleic acid halide used in the step (G) include chlorine atom, bromine atom, iodine atom and the like. A chlorine atom is particularly preferable as the halide.

Examples of the oleic acid ester used in the step (G) include methyl ester and ethyl ester.

The amount of the oleic acid compound used is not particularly limited, and is preferably in the range of 1 to 2 mol, particularly 1 to 1.5 mol, relative to 1 mol of the compound represented by the general formula (8). Is preferred.

As the step (G), for example, a method of reacting the cyclic phosphonic acid compound (8) with oleic acid in the presence of a condensing agent (step G-1);
A method of reacting a cyclic phosphonic acid compound (8) with an oleic acid halide in the presence of a base (step G-2);
A method of reacting a cyclic phosphonic acid compound (8) with oleic anhydride (step G-3);
Examples thereof include a method of reacting the cyclic phosphonic acid compound (8) with an oleic acid ester (step G-4).

The condensing agent used in Step G-1 is not particularly limited as long as it is a known condensing agent, and examples thereof include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. Hydrochloride (EDC) etc. are mentioned.

Examples of the base used in Step G-2 include organic bases such as triethylamine, pyridine, N,N-diethylaniline, 4-dimethylaminopyridine and diisopropylethylamine.

Examples of the step (G-1) include the following steps G-1A to G-1F.

Step G-1A: a method of reacting the cyclic phosphonic acid compound (8) and oleic acid in the presence of the condensing agent;
Step G-1B: a method of reacting the cyclic phosphonic acid compound (8) and oleic acid in the presence of 2-chloro-1-methylpyridinium iodide (CMPI);
Step G-1C: a method of reacting the cyclic phosphonic acid compound (8) with oleic acid in the presence of hexafluorophosphoric acid (benzotriazol-1-yloxy)tripyrrolidinophosphonium (pyBOP);
Step G-1D: The cyclic phosphonic acid compound (8) and oleic acid were combined with O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU). ) The reaction in the presence of;
Step G-1E: Cyclic phosphonic acid compound (8) and oleic acid were combined with O-(benzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HBTU). Method of reacting below;
Step G-1F: Cyclic phosphonic acid compound (8) and oleic acid were added in the presence of (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate (COMU). The method of reacting in step (G-2) can include, for example, the following step G-2A and step G-2B.

Step G-2A: a method of reacting the cyclic phosphonic acid compound (8) with an oleic acid halide in the presence of triethylamine;
Step G-2B: a method of producing an oleic acid halide from oleic acid, and reacting the oleic acid halide with the cyclic phosphonic acid compound (8) in the presence of triethylamine;
Examples of the step G-3 include the following step G-3A and step G-3B.

Step G-3A: Method of reacting cyclic phosphonic acid compound (8) with oleic acid anhydride; Step G-3B: Reacting oleic acid and tosylic acid chloride, and mixed acid anhydride of oleic acid in reaction system A method of reacting the acid anhydride with a cyclic phosphonic acid compound (8) after generating a compound, The condensing agent or base is usually 0.25 mol per 1 mol of the cyclic phosphonic acid compound (8). It can be used in any proportion up to an excess amount, preferably 0.5 to 2 mol. These condensing agents or bases are appropriately selected depending on the type of oleic acid compound or its derivative.

Step (G) can be performed in an atmosphere of an inert gas such as nitrogen or argon.

The reaction pressure is not particularly limited and can be carried out under normal pressure or under pressure.

The reaction temperature is generally 0 to 120°C, preferably 0 to 30°C, more preferably 15 to 25°C.

The reaction time is usually 0.1 to 100 hours, preferably 0.5 to 50 hours, and more preferably 2 to 17 hours.

After completion of the reaction, excess reagents (oleic acid compounds, etc.), unreacted raw material compounds, etc. are removed from the resulting reaction mixture by usual separation methods such as liquid separation, concentration, column purification, etc. The compound represented by (9) can be taken out. In addition, after completion of the reaction, only liquid separation and concentration are performed, and the mixture after the reaction can be used as it is in the step (H) without performing purification and isolation steps (telescoping synthesis).

Hereinafter, the present invention will be described in more detail with reference to Synthesis Examples, Examples and Comparative Examples, but the present invention is not limited to the following Examples.

[Process (A)]
Synthesis Example A1 (Step A: R ² =n-propyl)
Synthesis of 2,2-di-n-propyl-5-(hydroxymethyl)-1,3-dioxane (3b)

3.0 g of 2-hydroxymethyl-1,3 propanediol (2) was dissolved in 30 ml of tetrahydrofuran, 4.74 ml of 4-heptanone and 53.8 mg of p-toluenesulfonic acid monohydrate were added, and Dean-Stark was used. The mixture was heated under reflux for 3.5 hours. Further, during the reaction, tetrahydrofuran distilled off was discarded, and fresh tetrahydrofuran was added to the reaction mixture. After the reaction, 0.39 ml of triethylamine was added to the reaction mixture to stop the reaction, and tetrahydrofuran was distilled off under reduced pressure. 30 ml of ethyl acetate and 30 ml of water were added to the residue and the layers were separated. After extracting the organic layer, the aqueous layer was extracted twice more with 30 ml of ethyl acetate. The collected organic layer was washed with 30 ml of saturated brine, dried over magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain 2.34 g of acetal compound (3b) in a yield of 41%.
¹ H-NMR (500 MHz, CDCl ₃ ):
δ: 0.93 (m, 6H), 1.35 (m, 4H), 1.63 (m, 3H), 1.72 (m, 2H), 1.79 (m, 1H), 3.76. (M, 4H), 4.01 (dd, J=11.9, 4.0Hz, 2H)

Synthesis Example A2 (Step A: R ^Two = N-butyl)
Synthesis of 2,2-dibutyl-5-(hydroxymethyl)-1,3-dioxane (3c)

2-Hydroxymethyl-1,3 propanediol (2) 1.0 g is dissolved in tetrahydrofuran 9.5 ml, 5-nonanone 1.96 ml and p-toluenesulfonic acid monohydrate 17.9 mg are added, and it is for 17 hours. Heated to reflux. The reaction was stopped by adding 0.13 ml of triethylamine to the reaction mixture, and tetrahydrofuran was distilled off under reduced pressure. Ethyl acetate (10 ml) and water (10 ml) were added to the residue for liquid separation. After extracting the organic layer, the aqueous layer was extracted twice more with 10 ml of ethyl acetate. The collected organic layer was washed with 10 ml of saturated brine, dried over magnesium sulfate, filtered, and ethyl acetate was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain 156 mg of acetal compound (3c) in a yield of 7%.
¹ H-NMR (500 MHz, CDCl ₃ ):
δ: 0.92 (m, 6H), 1.31 (m, 8H), 1.50 (t, J=5.1Hz, 1H), 1.65 (m, 2H), 1.74 (m, 2H), 1.80 (m, 1H), 3.76 (m, 4H), 4.01 (dd, J=12.1, 4.1Hz, 2H)

Synthesis Example A3 (Step A: R ^Two = Phenyl)
Synthesis of 2,2-diphenyl-5-(hydroxymethyl)-1,3-dioxane (3d)

1.0 g of 2-hydroxymethyl-1,3 propanediol (2) was dissolved in 48 ml of DMF, 2.58 g of benzophenone dimethyl acetal and 656 mg of CSA were added, and the mixture was stirred at 40° C. under reduced pressure for 22.5 hours. DMF in the reaction mixture was distilled off under reduced pressure, and 10 ml of ethyl acetate and 10 ml of water were added to the residue for liquid separation. After extracting the organic layer, the aqueous layer was extracted twice more with 10 ml of ethyl acetate. The collected organic layer was washed with 10 ml of saturated saline. The extract was dried over magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to obtain 647 mg of acetal compound (3d) in a yield of 25%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.94 (m, 1H), 3.81 (dd, J=7.0, 5.2 Hz, 2H), 3.91 (dd, J=11.8, 5.5 Hz, 2H), 4 .14 (dd, J=11.8, 3.8 Hz, 2H), 7.25 (m, 2H), 7.34 (m, 4H), 7.51 (m, 4H)

[Process (B)]
Synthesis Example B1 (Step B: R ² =methyl)
Synthesis of 2,2-dimethyl-5-methanesulfonyloxymethyl-1,3-dioxane (4a)

2,2-Dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) (5.00 g) was dissolved in CH ₂ Cl _{2 (} 67 ml), triethylamine (5.42 ml) was added, and the mixture was cooled to -20°C. did. Further, 2.56 ml of mesyl chloride (MsCl) was added, and the mixture was stirred at -20°C for 1 hour. The reaction mixture was quenched with 50 ml of water and extracted twice with 40 ml of CH ₂ Cl ₂ . The separated organic layer was washed with water, CH ₂ Cl ₂ was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:1) to give the compound (4a ) 6.22 g was obtained with a yield of 92%.
¹ H-NMR (500 MHz, CDCl ₃ ):
δ: 1.39 (s, 3H), 1.46 (s, 3H), 2.00 (m, 1H), 3.04 (s, 3H), 3.78 (dd, 2H, J=12, 3Hz), 4.08 (dd, 2H, J=11.5, 2.5Hz), 4.42 (d, 2H, J=7Hz)

Synthesis Example B2 (Step B: R ^Two = N-propyl)
Synthesis of 2,2-di-n-propyl-5-methanesulfonyloxymethyl-1,3-dioxane (4b)

1.0 g of the compound (3b) obtained in Synthesis Example A1 was dissolved in 20 ml of CH ₂ Cl ₂ , 1.03 ml of triethylamine was further added, and the mixture was cooled to -20°C. Then, 0.459 ml of MsCl was added to the reaction solution, and the mixture was stirred at -20°C for 1 hour. The reaction mixture was added with 20 ml of water to stop the reaction, extracted twice with 20 ml of CH ₂ Cl ₂ and washed with 20 ml of saturated saline. Then, after drying over magnesium sulfate and filtering, CH ₂ Cl ₂ was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to obtain the compound (4b ) 1.27 g was obtained with a yield of 92%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.93 (m, 6H), 1.36 (m, 4H), 1.58 (m, 1H), 1.76 (m, 2H), 1.95 (m, 1H), 3.04 (S, 3H), 3.74 (dd, J=12.4, 3.3 Hz, 2H), 4.08 (dd, J=15.6, 3.3 Hz, 2H), 4.43 (d, J=7.5Hz, 2H)

Synthesis Example B3 (Step B: R ^Two = N-butyl)
Synthesis of 2,2-di-n-butyl-5-methanesulfonyloxymethyl-1,3-dioxane (4c)

156 mg of the compound (3c) obtained in Synthesis Example A2 was dissolved in 2.7 ml of CH ₂ Cl _2, 0.14 ml of triethylamine was further added, and the mixture was cooled to -20°C. Then, 0.062 ml of MsCl was added, and the mixture was stirred at -20°C for 1 hour. 1.8 ml of water was added to the obtained reaction mixture to stop the reaction, extraction was performed twice with 1.8 ml of CH ₂ Cl ₂ , and the organic layer was washed with 1.8 ml of saturated saline. Then, after drying over magnesium sulfate and filtering, CH ₂ Cl ₂ was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to obtain a compound ( 4c) 169 mg was obtained with a yield of 81%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.92 (m, 6H), 1.30 (m, 8H), 1.61 (m, 2H), 1.78 (m, 2H), 1.96 (m, 1H), 3.04 (S, 3H), 3.74 (dd, J=12.6, 3.6 Hz, 2H), 4.08 (dd, J=12.5, 3.5 Hz, 2H), 4.43 (d, J=7.4Hz, 2H)

Synthesis Example B4 (Step B: R ^Two = Phenyl)
Synthesis of 2,2-diphenyl-5-methanesulfonyloxymethyl-1,3-dioxane (4d)

640 mg of the compound (3d) obtained in Synthesis Example A3 was dissolved in 9.6 ml of CH ₂ Cl _2, 493 μl of triethylamine was further added, and the mixture was cooled to −20° C. Then, 220 μl of MsCl was added, and the mixture was stirred at −20° C. for 1 hour. Water 6.4 ml was added to the obtained reaction mixture to stop the reaction, extraction was performed twice with CH ₂ Cl ₂ 6.4 ml, and the organic layer was washed with saturated saline 6.4 ml. Then, after drying over magnesium sulfate and filtering, CH ₂ Cl ₂ was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=3:1) to give the compound (4d ) 729 mg was obtained with a yield of 88%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 2.06 (m, 1H), 3.03 (s, 3H), 3.95 (dd, J=12.2, 3.7 Hz, 2H), 4.18 (dd, J=12.2) , 3.4 Hz, 2H), 4.51 (d, J=7.5 Hz, 2H), 7.25 (m, 1H), 7.30 (m, 3H), 7.39 (m, 2H), 7.49 (m, 4H)

[Process (C)]
Synthesis Example C1-1 (Step C: R ² =methyl, base=TEA, solvent=methyl ethyl ketone) Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

400.0 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl ethyl ketone, 12 μl of triethylamine and 401.1 mg of sodium iodide were added, and the mixture was heated under reflux for 1.5 hours. Then, under reduced pressure, methyl ethyl ketone in the reaction mixture was distilled off, and CH ₂ Cl _{2 (} 10 ml) and water (10 ml) were added thereto for liquid separation. The aqueous layer was extracted twice with 10 ml of CH ₂ Cl ₂ , and the organic layer was washed by adding 5 ml of 5% sodium thiosulfate and 5 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 10 ml of water, and CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain 394.1 g of compound (5a) in a yield of 86%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.41 (s, 3H), 1.43 (s, 3H), 1.95 (m, 1H), 3.23 (d, J=7 Hz, 2H), 3.73 (dd, J=) 12, 6.5Hz, 2H), 4.01 (dd, J=11.5, 4Hz, 2H)

Synthesis Example C1-2 (Step C: R ^Two = N-propyl)
Synthesis of 2,2-di-n-propyl-5-iodomethyl-1,3-dioxane (5b)

1.20 g of the compound (4b) obtained in Synthesis Example B2 was dissolved in 14.3 ml of methyl ethyl ketone, 30 μl of triethylamine and 966 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Methyl ethyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (} 15 ml) and water (15 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 15 ml of CH ₂ Cl ₂ , and the organic layer was washed with 7.5 ml of 5% sodium thiosulfate and 7.5 ml of 1% aqueous sodium hydrogen carbonate solution. Further, the organic layer was washed with 15 ml of saturated saline. Then, after drying over magnesium sulfate and filtering, CH ₂ Cl ₂ was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain a compound ( 5b) 1.16 g was obtained with a yield of 86%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.93 (t, J=7.3 Hz, 6H), 1.35 (m, 4H), 1.66 (m, 4H), 1.90 (m, 1H), 3.25 (d, J=7.2 Hz, 2H), 3.71 (dd, J=11.8, 6.0 Hz, 2H), 4.01 (dd, J=11.9, 3.9 Hz, 2H)

Synthesis Example C1-3 (Step C: R ^Two = N-butyl)
Synthesis of 2,2-di-n-butyl-5-iodomethyl-1,3-dioxane (5c)

169 mg of the compound (4c) obtained in Synthesis Example B3 was dissolved in 2.9 ml of methyl ethyl ketone, 3.8 μl of triethylamine and 123 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Then, methyl ethyl ketone in the reaction solution was distilled off under reduced pressure, and CH ₂ Cl _{2 (} 3 ml) and water (3 ml) were added to separate the layers. Then, the aqueous layer was extracted twice with 3 ml of CH ₂ Cl ₂ and the organic layer was washed with 1.5 ml of 5% sodium thiosulfate and 1.5 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 3 ml of saturated saline. Then, after drying with magnesium sulfate and filtering, CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 139 mg of compound (5c) in a yield of 75%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.92 (m, 6H), 1.30 (m, 8H), 1.68 (m, 4H), 1.91 (m, 1H), 3.25 (d, J=7.2Hz, 2H), 3.71 (dd, J=12.0, 6.2 Hz, 2H), 4.00 (dd, J=11.9, 4.0 Hz, 2H)

Synthesis Example C1-4 (Step C: R ^Two = Phenyl)
Synthesis of 2,2-diphenyl-5-iodomethyl-1,3-dioxane (5d)

729 mg of the compound (4d) obtained in Synthesis Example B4 was dissolved in 10.9 ml of methyl ethyl ketone, 14.5 μl of triethylamine and 470 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Methyl ethyl ketone in the reaction solution was distilled off under reduced pressure, and CH ₂ Cl _{2 (} 5 ml) and water (5 ml) were added to separate the layers. The aqueous layer was extracted twice with 3 ml of CH ₂ Cl ₂ , and the organic layer was washed with 2.5 ml of 5% sodium thiosulfate and 2.5 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 5 ml of saturated saline. Then, after drying with magnesium sulfate and filtering, CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 726 mg of compound (5d) in a yield of 91%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 2.10 (m, 1H), 3.25 (d, J=7.5 Hz, 2H), 3.84 (dd, J=11.7, 6.3 Hz, 2H), 4.16 (dd , J=11.7, 3.8 Hz, 2H), 7.26 (m, 2H), 7.34 (m, 4H), 7.50 (m, 4H).

Synthesis example C2-1 (step C: solvent = acetone + methyl isobutyl ketone)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 3 ml of acetone and 3 ml of methyl isobutyl ketone under an argon atmosphere, 9.3 μl of triethylamine and 301 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Acetone and methyl isobutyl ketone in the reaction solution were distilled off under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added thereto, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 266 mg of compound (5a) in a yield of 78%.

Synthesis example C2-2 (step C: solvent=acetone)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of acetone under an argon atmosphere, 9.3 μl of triethylamine and 301 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Acetone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 204 mg of compound (5a) in a yield of 59%.

Synthesis example C2-3 (step C: solvent = methyl isobutyl ketone)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl isobutyl ketone under an argon atmosphere, 9.3 μl of triethylamine and 301 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Methyl isobutyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 190 mg of compound (5a) in a yield of 55%.

Synthesis Example C3-1 (Step C: alkali metal halide = sodium bromide)
Synthesis of 2,2-dimethyl-5-bromomethyl-1,3-dioxane (5a-1)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl ethyl ketone under an argon atmosphere, 9.3 μl of triethylamine and 207 mg of sodium bromide were added, and the mixture was heated under reflux for 23 hours. Methyl ethyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 127 mg of compound (5a-1) in a yield of 45%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.41 (s, 3H), 1.44 (s, 3H), 2.02 (m, 1H), 3.51 (d, J=7.1 Hz, 2H), 3.80 (dd, J=12,5.7 Hz, 2H), 4.05 (dd, J=12,4 Hz, 2H)

Synthesis example C4-1 (step C: base = diisopropylethyleneamine)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl ethyl ketone under an argon atmosphere, 12 μl of diisopropylethyleneamine and 301 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Methyl ethyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 262 mg of compound (5a) in a yield of 78%.

Synthesis Example C4-2 (Step C: base=sodium hydrogen carbonate, solvent=methyl ethyl ketone) Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl ethyl ketone under an argon atmosphere, 5.6 mg of sodium hydrogen carbonate and 301 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Methyl ethyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 234 mg of compound (5a) in a yield of 68%.

Synthesis Example C4-3 (Step C: base = NaHCO3 _Three , Solvent = acetone)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

15.0 g of the compound (4a) obtained in Synthesis Example B1 was dissolved in 225 ml of acetone, and 5.62 g of sodium hydrogen carbonate and 20.05 g of sodium iodide were added, and the mixture was heated under reflux for 19 hours. Then, the white solid was filtered and washed with acetone, and then acetone was distilled off under reduced pressure, 150 ml of CH ₂ Cl ₂ was added thereto, and 50 ml of 5% sodium thiosulfate and 50 ml of 1% aqueous sodium hydrogen carbonate solution were added to the organic layer. In addition, liquid separation was performed. It was extracted with 50 ml of CH ₂ Cl ₂ , the organic layer was washed with 5% brine, and CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain 14.00 g of compound (5a) in a yield of 82%.

Synthesis example C4-4 (step C: base = potassium hydrogen carbonate)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl ethyl ketone under an argon atmosphere, 6.7 mg of potassium hydrogen carbonate and 301 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Methyl ethyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 106 mg of compound (5a) in a yield of 31%.

Synthesis example C4-5 (step C: base = potassium carbonate)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl ethyl ketone under an argon atmosphere, potassium carbonate and 301 mg of sodium iodide were further added, and the mixture was heated under reflux for 2 hours. Methyl ethyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 209 mg of compound (5a) in a yield of 61%.

Synthesis example C4-6 (step C: base = sodium carbonate)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

300 mg of the compound (4a) obtained in Synthesis Example B1 was dissolved in 6 ml of methyl ethyl ketone under an argon atmosphere, further sodium carbonate and 301 mg of sodium iodide were added, and the mixture was heated under reflux for 2 hours. Methyl ethyl ketone in the reaction solution was evaporated under reduced pressure, CH ₂ Cl _{2 (6} ml) and water (6 ml) were added, and the layers were separated. The aqueous layer was extracted twice with 6 ml of CH ₂ Cl ₂ and the organic layer was washed with 3 ml of 5% sodium thiosulfate and 3 ml of 1% aqueous sodium hydrogen carbonate. Further, the organic layer was washed with 6 ml of saturated saline and dried over magnesium sulfate, and then CH ₂ Cl ₂ was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=10:1) to obtain 270 mg of compound (5a) in a yield of 79%.

[Process (B')]
Synthesis example B1 (step B′: solvent=dichloromethane)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

1.00 g of 2,2-dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) was dissolved in 22.8 ml of dichloromethane (MDC), and 700.0 mg of imidazole and 2.08 g of iodine were added thereto. After cooling to 0° C., 2.15 g of triphenylphosphine was subsequently added, and the mixture was stirred at 25° C. for 2 hours. Then, it was quenched with 20 ml of water, extracted twice with 10 ml of dichloromethane, and washed with 20 ml of water. Dichloromethane was distilled off from the organic phase under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain 2,2-dimethyl-5-iodomethyl-1,3-. 1.38 g of dioxane (5a) was obtained with a yield of 79%.

Synthesis example B2 (step B': solvent = THF)
Synthesis of 2,2-dimethyl-5-iodomethyl-1,3-dioxane (5a)

500.0 mg of 2,2-dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) was dissolved in 3.4 ml of tetrahydrofuran, and after cooling to 0°C, 1.08 g of triphenylphosphine and 279 of imidazole were added thereto. 0.5 mg and 1.04 g of iodine were added, and the mixture was stirred at 25° C. for 2.5 hours. Then, it was washed with 10% of 5% aqueous sodium thiosulfate solution, extracted with 20 ml of ethyl acetate, and washed with 5% saline. The organic phase was dried over magnesium sulfate, filtered, and ethyl acetate was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain 2,2-dimethyl. 639.0 mg of -5-iodomethyl-1,3-dioxane (5a) was obtained with a yield of 73%.

Synthesis example B3 (step B': solvent = CPME)
Synthesis of 2,2-dimethyl-5-bromomethyl-1,3-dioxane (5a)

500.0 mg of 2,2-dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) was dissolved in 6.8 ml of tetrahydrofuran and, after cooling to 0° C., 1.08 g of triphenylphosphine and 279.5 mg of imidazole. , And 1.04 g of iodine were added, and the mixture was stirred at 25° C. for 2 hours. Then, triphenylphosphine oxide was removed, and after washing with 10 ml of CPME, the organic phase was washed with 10 ml of a 5% sodium thiosulfate aqueous solution, extracted 3 times with 10 ml of CPME, and washed with 5% saline. CPME was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain 2,2-dimethyl-5-bromomethyl-1,3-dioxane (5a ) 621.1 mg was obtained with a yield of 71%.

Synthesis example B4 (step B': solvent = dichloromethane)
Synthesis of 2,2-dimethyl-5-bromomethyl-1,3-dioxane (5b)

2,2-Dimethyl-5-(hydroxymethyl)-1,3-dioxane (3a) (1.00 g) was dissolved in dichloromethane (MDC) 22.8 ml, and imidazole 700.0 mg and carbon tetrabromide 2. After adding 72 g and cooling with ice, 2.15 g of triphenylphosphine was subsequently added and the mixture was stirred at room temperature for 4 hours. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=5:1) to obtain 1.60 g of 2,2-dimethyl-5-bromomethyl-1,3-dioxane (5b). Obtained quantitatively.

[Process (D)]
Synthesis example D1-1 (step D: R ² = methyl)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

300.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 2.34 ml of DMF, 763.4 mg of cesium carbonate and 215 μl of dimethyl phosphite were added, and the mixture was stirred at 40° C. for 5 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 5 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 5 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 255.6 mg of dimethyl phosphonate compound (6a). Was obtained with a yield of 92%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.42 (s, 6H), 1.82 (dd, J=18.5, 6.5Hz, 2H), 2.15 (m, 1H), 3.66 (dd, J=11.5) , 7Hz, 2H), 3.75 (d, J = 10.5Hz, 6H), 4.01 (d, J = 12, 3.5Hz, 2H)

Synthesis Example D1-2 (Step D: R ^Two = N-propyl)
Synthesis of (2,2-di-n-propyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6b)

1.06 g of the iodine compound (5b) obtained in Synthesis Example C1-2 was dissolved in 6.8 ml of DMF, 2.21 g of cesium carbonate and 621 μl of dimethyl phosphite were added, and the mixture was stirred at 40° C. for 3 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 5 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 2.5 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give phosphonic acid dimethyl compound (6b) (767 mg). Was obtained with a yield of 79%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.91 (t, J = 7.4 Hz, 6H), 1.36 (m, 4H), 1.66 (m, 4H), 1.84 (dd, J = 18.7, 6.9Hz). , 2H), 2.09 (m, 1H), 3.63 (dd, J = 11.7, 6.6Hz, 2H), 3.75 (d, J = 10.9Hz, 6H), 3.99. (Dd, J=11.7, 3.8 Hz, 2H)

Synthesis Example D1-3 (Step D: R ^Two = Butyl)
Synthesis of (2,2-dibutyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6c)

139 mg of the iodine compound (5c) obtained in Synthesis Example C1-3 was dissolved in 1.2 ml of DMF, 266 mg of cesium carbonate and 75 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 1 ml of toluene, and the white solid was filtered. The white solid was further washed with 1 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give 80.5 mg of dimethyl phosphonate compound (6c). Was obtained in a yield of 61%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.91 (m, 6H), 1.30 (m, 8H), 1.68 (m, 4H), 1.83 (dd, J=18.7, 6.9Hz, 2H), 2. 10 (m, 1H), 3.63 (dd.J=11.8, 6.7 Hz, 2H), 3.75 (d, J=10.9 Hz, 6H), 3.99 (dd, J=11) .7, 3.9 Hz, 2H)

Synthesis Example D1-4 (Step D: R ^Two = Phenyl)
Synthesis of (2,2-diphenyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6d)

726 mg of the iodine compound (5d) obtained in Synthesis Example C1-4 was dissolved in 5.7 ml of DMF, 1.24 g of cesium carbonate and 350 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 4.2 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 2.1 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 621 mg of dimethyl phosphonate compound (6d). Was obtained with a yield of 90%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.80 (dd, J=18.8, 7.0 Hz, 2H), 2.30 (m, 1H), 3.74 (d, J=10.9 Hz, 6H), 3.77 (dd , J=11.5, 7.2 Hz, 2H), 4.15 (dd, J=11.5, 3.8 Hz, 2H), 7.26 (m, 2H), 7.33 (m, 4H). , 7.50 (m, 4H)

Synthesis Example D2-1 (Step D: R ^Two = Methyl, solvent = DMF)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of DMF, 1.27 g of cesium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 406.0 mg of dimethyl phosphonate compound (6a). Was obtained with a yield of 87%.

Synthesis Example D2-2 (Step D: R ^Two = Methyl, solvent = DMAc)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of DMAc, 1.27 g of cesium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. The DMAc in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 438.7 mg of dimethyl phosphonate compound (6a). Was obtained with a yield of 94%.

Synthesis Example D2-3 (Step D: R ^Two = Methyl, solvent = acetonitrile)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of acetonitrile, 1.27 g of cesium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 24 hours. .. Acetonitrile in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 20 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 408.8 mg of dimethyl phosphonate compound (6a). Was obtained with a yield of 88%.

Synthesis Example D2-4 (Step D: R ^Two = Methyl, solvent = DMF/AN (1/1))
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 2.0 ml of DMF and 2.0 ml of acetonitrile, 1.27 g of cesium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was heated at 50° C. Stir for 18 hours. The solvent in the reaction solution was evaporated under reduced pressure, the resulting residue was replaced with 20 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 404.1 mg of dimethyl phosphonate compound (6a). Was obtained with a yield of 87%.

Synthesis Example D3-1 (Process D: R ^Two = Methyl, base = cesium carbonate)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of DMF, 1.27 g of cesium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 406.0 mg of dimethyl phosphonate compound (6a). Was obtained with a yield of 87%.

Synthesis Example D3-2 (Step D: R ^Two = Methyl, base = potassium carbonate)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of DMF, 540 mg of potassium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 24 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 139.6 mg of dimethyl phosphonate compound (6a). Was obtained in a yield of 30%.

Synthesis Example D3-3 (Step D: R ^Two = Methyl, base = rubidium carbonate)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of DMF, 902.1 mg of rubidium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 24 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give 280.7 mg of dimethyl phosphonate compound (6a). Was obtained in a yield of 60%.

Synthesis Example D3-4 (Step D: R ^Two = Methyl, base = sodium carbonate)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of DMF, 414.0 mg of sodium carbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 24 hours. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, the residue was made up to 5 ml of toluene, and liquid quantification was performed. The yield was 1.2%.

Synthesis Example D3-5 (Step D: R ^Two = Methyl, base = potassium hydrogen carbonate)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

500.0 mg of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 3.9 ml of DMF, 391.1 mg of potassium hydrogencarbonate and 360 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 24 hours. .. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, the residue was made up to 5 ml of toluene, and liquid quantification was performed. The yield was 3.5%.

Synthesis Example D4-1 (Step D: X=bromine)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid dimethyl ester (6a)

93.7 mg of the bromine compound (5a-1) obtained in Synthesis Example C3-1 was dissolved in 0.9 ml of DMF, 292 mg of cesium carbonate and 82.1 μl of dimethyl phosphite were added, and the mixture was stirred at 50° C. for 4 hours. did. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 5 ml of toluene, and the white solid was filtered. The white solid was further washed with 10 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give 89.3 mg of dimethyl phosphonate compound (6a). Was obtained with a yield of 84%.

Synthesis Example D5-1 (Process D: R ¹ = Ethyl)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid diethyl ester (6a-1)

2.00 g of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 15.6 ml of DMF, 5.09 g of cesium carbonate and 2.01 ml of diethyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. did. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 20 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 30 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain a diethyl phosphonate compound (6a-1) 2 .24 g was quantitatively obtained.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.33 (t, J=7 Hz, 6H), 1.42 (s, 3H), 1.42 (s, 3H), 1.76 (dd, J=19,7 Hz, 2H), 2. 18 (m, 1H), 3.66 (dd, J=11.5, 7.5 Hz, 2H), 4.00 (dd, J=11.5, 4 Hz, 2H), 4.10 (m, 4H) )

Synthesis Example D5-2 (Step D: R ¹ = N-butyl)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid diethyl ester (6a-2)

2.00 g of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 15.6 ml of DMF, 5.09 g of cesium carbonate and 3.05 ml of dibutyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. did. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 20 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 20 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain a dibutyl phosphonate compound (6a-2) 2 0.74 g was quantitatively obtained.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.94 (t, J=7.5 Hz, 6H), 1.40 (tq, J=7.5, 7.5 Hz, 4H), 1.42 (s, 6H), 1.65 (tt , J=8, 8 Hz, 4H), 1.75 (dd, J=19,7 Hz, 2H), 2.17 (m, 1H), 3.66 (dd, J=11.5, 7.5 Hz, 2H), 4.03 (m, 6H)

Synthesis Example D5-3 (Step D: R ¹ = Ethyl)
Synthesis of (2,2-dimethyl-[1,3]dioxan-5-ylmethyl)-phosphonic acid diethyl ester (6a-3)

1.00 g of the iodine compound (5a) obtained in Synthesis Example C1-1 was dissolved in 7.8 ml of DMF, 2.54 g of cesium carbonate and 1.74 ml of dibenzyl phosphite were added, and the mixture was stirred at 50° C. for 3 hours. did. DMF in the reaction solution was distilled off under reduced pressure, the resulting residue was replaced with 10 ml of toluene, and the white solid was filtered. Further, the white solid was washed with 20 ml of toluene, the obtained filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:2) to obtain the dibenzyl phosphonate compound (6a- 3) 1.58 g was quantitatively obtained.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.38 (s, 3H), 1.39 (s, 3H), 1.77 (dd, J=19,7 Hz, 2H), 2.11 (m, 1H), 3.58 (dd, J=11.5,7Hz,2H),3.93(dd,12,4Hz,2H),5.00(m,4H),7.34(m,10H)

[Process (E)]
Synthesis Example E1-1 (Step E: R ² =methyl)
Synthesis of (2,3-dihydroxypropyl)-phosphonic acid dimethyl ester (7a)

5.00 g of phosphonic acid dimethyl compound (6a) obtained in Synthesis Example D1-1 was dissolved in 125 ml of methanol, 798.5 mg of p-toluenesulfonic acid monohydrate was further added, and the mixture was stirred at 20° C. for 3 hours. did. The reaction was stopped with 640 μl of triethylamine, and the methanol in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 3.82 g of the diol compound (7a) in a yield of 92%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.93 (dd, J=18.5, 7 Hz, 2H), 2.13 (m, 1H), 2.87 (dd, J=6, 6 Hz, 2H), 3.77 (m, 10H) )

Synthesis Example E1-2 (Step E: R ^Two = N-propyl)
Synthesis of 2-(dimethylphosphono)methyl-1,3-propanediol (7a)

687 mg of the dimethyl phosphonate compound (6b) obtained in Synthesis Example D1-2 was dissolved in 4.7 ml of methanol, 22.0 mg of p-toluenesulfonic acid monohydrate was further added, and the mixture was stirred at 20° C. for 3 hours. did. The methanol in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=5:1) to obtain 361 mg of the diol compound (7a) with a yield of 78%.

Synthesis Example E1-3 (Step E: R ^Two = Butyl)
Synthesis of 2-(dimethylphosphono)methyl-1,3-propanediol (7a)

80.5 mg of the dimethyl phosphonate compound (6c) obtained in Synthesis Example D1-3 was dissolved in 0.75 ml of methanol, 2.4 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was mixed at 20° C. for 3 days. Stir for hours. The methanol in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 37.5 mg of the diol compound (7a) with a yield of 76%.

Synthesis Example E1-4 (Step E: R ^Two = Phenyl)
Synthesis of 2-(dimethylphosphono)methyl-1,3-propanediol (7a)

621 mg of the phosphonic acid dimethyl compound (6d) obtained in Synthesis Example D1-4 was dissolved in 5.1 ml of methanol, and 16.3 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was heated at 0° C. for 15 hours. The mixture was stirred at 20°C for 1 hour. The methanol in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 226 mg of the diol compound (7a) with a yield of 67%.

Synthesis Example E2-1 (Step E: R ^Two = Ethyl)
Synthesis of 2-(diethylphosphono)methyl-1,3-propanediol (7a-1)

2.00 g of the diethyl phosphonate compound (6a-1) obtained in Synthesis Example D5-1 was dissolved in 15 ml of methanol, and 428.6 mg of p-toluenesulfonic acid monohydrate was further added, followed by 3 at 20°C. Stir for hours and then at 0° C. overnight. Methanol in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:methanol=5:1) to obtain 1.69 g of diol compound (7a-1) in a yield of 99%. Obtained.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.34 (t, J=7 Hz, 6 H), 1.91 (dd, J=18.5, 7 Hz, 2 H), 2.14 (m, 1 H), 3.20 (br, hydroxyl group), 3.77 (d, J=5 Hz, 4H), 4.12 (m, 4H)

Synthesis Example E2-2 (Step E: R ^Two = N-butyl)
Synthesis of 2-(dibutylphosphono)methyl-1,3-propanediol (7a-2)

2.50 g of dibutyl phosphonate compound (6a-2) obtained in Synthesis Example D5-2 was dissolved in 15.5 ml of methanol, and 442.5 mg of p-toluenesulfonic acid monohydrate was further added, and the mixture was heated at 20°C. And stirred for 8 hours. Methanol in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 2.13 g of the diol compound (7a-2) in a yield of 97%. Obtained.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.94 (t, J=7.5 Hz, 6H), 1.41 (tq, J=7.5, 7.5 Hz, 4H), 1.66 (tt, J=8, 8 Hz, 4H) , 1.90 (dd, J=19, 7 Hz, 2H), 2.12 (m, 1H), 3.76 (m, 4H), 4.04 (m, 4H)

Synthesis Example E2-3 (Step E: R ^Two = Benzyl)
Synthesis of 2-(dibenzylphosphono)methyl-1,3-propanediol (7a-3)

1.58 g of the dibenzyl phosphonate compound (6a-3) obtained in Synthesis Example D5-3 was dissolved in 8.1 ml of methanol, and 230.9 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was heated at 20°C. Stirred for 3 hours and then at 0° C. overnight. Methanol in the reaction solution was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 1.27 g of the diol compound (7a-3) in a yield of 89%. Obtained.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.92 (dd, J=19,7 Hz, 2H), 2.05 (m, 1H), 3.70 (m, 4H), 5.01 (m, 4H), 7.34 (m, 10H)

[Process (F)]
Synthesis example F1-1 (step F: base=DBU, solvent=DMF)
Synthesis of (2-methoxy-2-oxo-2λ ⁵ -[1,2]oxaphospholan-4-yl)methanol (8a)

200.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 4 ml of DMF, 45.3 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped by adding 57.6 mg of p-toluenesulfonic acid monohydrate to the reaction mixture, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=9:1) to obtain 147.1 mg of a cyclic phosphonic acid compound (8a) with a yield of 88%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.73-2.07 (m, 3H), 2.35 (dd, J=5, 5 Hz, 1H), 2.68-2.88 (m, 1H), 3.65-3.73. (M, 2H), 3.79 (dd, J=11, 3.5 Hz, 3H), 3.89-4.37 (m, 2H)

Synthesis Example F1-2 (Step F: base=DBU, solvent=DMAc)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10.2 ml of dimethylformacetamide, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and dimethylformacetamide in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=5:1) to obtain 212 mg of a cyclic phosphonic acid compound (8a) with a yield of 51%.

Synthesis example F1-3 (step F: base=DBU, solvent=acetonitrile (AN))
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10.2 ml of acetonitrile, 113 μl of DBU was further added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and acetonitrile in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 235 mg of cyclic phosphonic acid compound (8a) with a yield of 56%.

Synthesis example F1-4 (step F: base=DBU, solvent=acetone)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10.2 ml of acetone, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and acetone in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 224 mg of cyclic phosphonic acid compound (8a) with a yield of 54%.

Synthesis example F1-4 (step F: base=DBU, solvent=methanol)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10.2 ml of methanol, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and methanol in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 86.8 mg of cyclic phosphonic acid compound (8a) in a yield of 21%.

Synthesis example F1-5 (step F: base=DBU, solvent=isopropanol)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10.2 ml of isopropanol, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and isopropanol in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 75 mg of cyclic phosphonic acid compound (8a) in a yield of 18%.

Synthesis example F1-6 (step F: base=DBU, solvent=butanol)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10.2 ml of butanol, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and butanol in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 121 mg of the cyclic phosphonic acid compound (8a) in a yield of 29%.

Synthesis example F1-7 (step F: base=DBU, solvent=DMF/acetonitrile)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 5.1 ml of DMF and 5.1 ml of acetonitrile, 113 μl of DBU was further added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF and acetonitrile in the reaction solution were distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 170 mg of the cyclic phosphonic acid compound (8a) in a yield of 41%.

Synthesis Example F2-1 (Step F: base = DBU (0.3 eq.), solvent = DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 304.7 mg of cyclic phosphonic acid compound (8a) with a yield of 73%.

Synthesis example F2-2 (step F: base = DBN (0.3 eq.), solvent = DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 90 μl of DBN was further added, and the mixture was stirred at 20° C. for 4 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 307.2 mg of cyclic phosphonic acid compound (8a) with a yield of 73%.

Synthesis example F2-3 (step F: base = TEA (0.3 eq.), solvent = DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 105 μl of TEA was further added, the temperature was raised from 20° C. to reflux, and then the mixture was stirred for 2.5 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 216.2 mg of cyclic phosphonic acid compound (8a) with a yield of 52%.

Synthesis example F2-4 (step F: base = DIPEA (0.3 eq.), solvent = DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 132 μl of DIPEA was further added, the temperature was raised from 20° C. to reflux under heating, and then the mixture was stirred for 2.5 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 226.1 mg of cyclic phosphonic acid compound (8a) with a yield of 54%.

Synthesis example F2-5 (step F: base = NaOMe (0.3 eq.), solvent = DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 40.9 mg of sodium methoxide was further added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. 10 ml of chloroform was added to the residue, white salts were filtered, the white solid was washed with 10 ml of chloroform, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 258.1 mg of the cyclic phosphonic acid compound (8a) at a yield of 62%.

Synthesis example F2-6 (step F: base = NaOEt (0.3 eq.), solvent = DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

770.7 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 15.4 ml of DMF, 79.4 mg of sodium ethoxide was further added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 221.9 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. 20 ml of chloroform was added to the residue, a white salt was filtered, the white solid was washed with 20 ml of chloroform, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 349.0 mg of a cyclic phosphonic acid compound (8a) with a yield of 54%.

Synthesis example F2-7 (step F: base = t-BuOK (0.3 eq.), solvent = DMF) (2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 84.9 mg of potassium tert-butoxide was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. 10 ml of chloroform was added to the residue, white salts were filtered, the white solid was washed with 10 ml of chloroform, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 193.8 mg of cyclic phosphonic acid compound (8a) with a yield of 46%.

Synthesis Example F2-8 (Step F: base = t-BuONa (0.3 eq.), solvent = DMF) (2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 72.7 mg of sodium tert-butoxide was further added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and the precipitated white solid was removed by filtration. The white solid was washed with 5 ml of DMF, and the filtrate was evaporated under reduced pressure to remove DMF. 10 ml of chloroform was added to the residue, white salts were filtered, washed with 10 ml of chloroform, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 200.6 mg of cyclic phosphonic acid compound (8a) in a yield of 48%.

Synthesis Example F2-9 (Step F: base=CsCO _Three (0.3 eq., solvent=DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 246.6 mg of cesium carbonate was further added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. 10 ml of chloroform was added to the residue, white salts were filtered, the white solid was washed with 10 ml of chloroform, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 35.1 mg of cyclic phosphonic acid compound (8a) in a yield of 8%.

Synthesis example F2-10 (step F: base = NaH (0.3 eq.), solvent = DMF)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 30.3 mg of sodium hydride was further added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 144 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. 10 ml of chloroform was added to the residue, white salts were filtered, the white solid was washed with 10 ml of chloroform, and the filtrate was concentrated. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 190.2 mg of cyclic phosphonic acid compound (8a) in a yield of 45%.

Synthesis example F3-1 (step F: quenching agent=CSA)
(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a)

500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 175.9 mg of camphorsulfonic acid (CSA), and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to quantitatively obtain 554.2 mg of the cyclic phosphonic acid compound (8a).

Synthesis example F3-2 (step F: quenching agent = formic acid)
500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 30 μl of formic acid, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 305.6 mg of cyclic phosphonic acid compound (8a) with a yield of 73%.

Synthesis example F3-3 (step F: quenching agent = acetic acid)
500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 43 μl of acetic acid, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 289.6 mg of cyclic phosphonic acid compound (8a) with a yield of 69%.

Synthesis example F3-4 (step F: quenching agent=propionic acid)
500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 57 μl of propionic acid, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 303.0 mg of cyclic phosphonic acid compound (8a) with a yield of 72%.

Synthesis example F3-5 (step F: quenching agent = butyric acid)
500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 69 μl of butyric acid, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 303.3 mg of the cyclic phosphonic acid compound (8a) with a yield of 72%.

Synthesis example F3-6 (step F: quenching agent = trifluoroacetic acid)
500.0 mg of the diol compound (7a) obtained in Synthesis Example E1-1 was dissolved in 10 ml of DMF, 113 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. The reaction was stopped with 58 μl of trifluoroacetic acid, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 288.4 mg of cyclic phosphonic acid compound (8a) with a yield of 69%.

Synthesis Example F4-1 (Step F: base=DBU, solvent=acetonitrile (AN))
(2-ethoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a-1)

1.50 g of the diol compound (7a-1) obtained in Synthesis Example E2-1 was dissolved in 26.5 ml of DMF, 297 μl of DBU was further added, and the mixture was stirred at 20° C. for 3 hours. Further, 200 μl of DBU was added to this solution, and the mixture was stirred at 20° C. for 2 hours. Then, the reaction was stopped with 630.7 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1). The obtained fraction was again dissolved in 25.1 ml of DMF, 282 μl of DBU was added, and the mixture was stirred at 20° C. for 4 hours. Further, 282 μl of DBU was added to this solution, and the mixture was stirred at 20° C. for 3 hours. Subsequently, 282 μl of DBU was added, the mixture was stirred at 20° C. for 3 hours, the reaction was stopped with 1.08 g of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 781.6 mg of cyclic phosphonic acid compound (8a-1) at a yield of 69%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.35 (t, J=7 Hz, 3H), 1.75 (m, 1H), 1.85 (br, hydroxyl group), 2.00 (m, 1H), 2.15 (br, hydroxyl group). , 2.78 (m, 1H), 3.70 (m, 2H), 3.89-4.36 (m, 4H)

Synthesis Example F4-2 (Step F: base=DBU, solvent=acetonitrile (AN))
(2-ethoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a-1)

1.50 g of the diol compound (7a-1) obtained in Synthesis Example E2-1 was dissolved in 26.5 ml of DMF, 297 μl of DBU was further added, and the mixture was stirred at 20° C. for 3 hours. Further, 200 μl of DBU was added to this solution, and the mixture was stirred at 20° C. for 2 hours. Then, the reaction was stopped with 630.7 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1). The obtained fraction was again dissolved in 25.1 ml of DMF, 282 μl of DBU was added, and the mixture was stirred at 20° C. for 4 hours. Further, 282 μl of DBU was added to this solution, and the mixture was stirred at 20° C. for 3 hours. Subsequently, 282 μl of DBU was added, the mixture was stirred at 20° C. for 3 hours, the reaction was stopped with 1.08 g of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 781.6 mg of cyclic phosphonic acid compound (8a-1) at a yield of 69%.

Synthesis example F4-3 (step F: R1=n-Bu)
(2-butoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a-2)

1.72 g of the diol compound (7a-2) obtained in Synthesis Example E2-2 was dissolved in 24.4 ml of DMF, 911 μl of DBU was further added, and the mixture was stirred at 60° C. for 5 hours. Then, the reaction was stopped with 1.16 g of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=10:1) to obtain 1.03 g of the cyclic phosphonic acid compound (8a-2) with a yield of 81%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.94 (t, J=7.5 Hz, 6H), 1.40 (tq, J=7.5, 7.5 Hz, 4H), 1.64-1.79 (m, 3H), 2 0.000 (m, 1H), 2.36 (br, hydroxyl group), 2.69-2.89 (m, 1H), 3.70 (m, 2H), 3.89-4.36 (m, 2H). ), 4.10 (m, 2H)

Synthesis Example F4-4 (Step F: R1=benzyl)
(2-benzyloxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methanol (8a-3)

350.4 mg of the diol compound (7a-3) obtained in Synthesis Example E2-3 was dissolved in 4 ml of DMF, 45 μl of DBU was added, and the mixture was stirred at 20° C. for 3 hours. Then, the reaction was stopped with 57.1 mg of p-toluenesulfonic acid monohydrate, and DMF in the reaction solution was distilled off under reduced pressure. The obtained residue was purified by silica gel chromatography (chloroform:methanol=5:1) to obtain 188.5 mg of cyclic phosphonic acid compound (8a-3) with a yield of 78%.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 1.65 to 2.06 (m, 2H), 2.66 to 2.80 (m, 1H), 3.61 to 3.67 (m, 2H), 3.88 to 4.36 (m , 2H), 5.12 (m, 2H), 7.33-7.41 (m, 5H)

[Process (G)]
Synthesis example G1-1 (step G: solvent=dichloromethane)
Synthesis of 9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ -[1,2]oxaphosphoran-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of dichloromethane, 510.1 mg of oleic acid and 66.2 mg of DMAP were added, and the mixture was cooled to 0°C. Then, 415.4 mg of EDC was added to this solution, and the mixture was stirred at room temperature for 2.5 hours. The reaction was stopped with 10 ml of 1N hydrochloric acid, the layers were separated, extracted with 10 ml of dichloromethane, extracted again with 5 ml of dichloromethane, and the organic phase was washed with 10 ml of 1% saline. Then, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain phosphonate compound (9a) (649.8 mg) at a yield of 84%.
¹ H-NMR (500 MHz, CDCl ₃ ):
δ: 0.88 (t, J=6.5 Hz, 3H), 1.27-1.30 (m, 20H,), 1.60-1.76 (m, 3H) 2.01-2.12 (M, 5H), 2.32 (t, J=7.5Hz, 2H), 2.83-2.97 (m, 1H), 3.78-4.34 (m, 7H), 5.31. -5.38 (m, 2H)

Synthesis example G1-2 (step G: solvent=toluene)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of toluene, 510.1 mg of oleic acid and 66.2 mg of DMAP were further added, and the mixture was cooled to 0°C. Then, 415.4 mg of EDC was added to this solution, and the mixture was stirred at room temperature for 4 hours. The reaction was stopped with 10 ml of 1N hydrochloric acid, 2 ml of methanol was added, and after liquid separation, extraction was performed 3 times with 10 ml of toluene, and the organic phase was washed with 10 ml of 1% saline. Then, toluene was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 369.1 mg of phosphonate compound (9a) at a yield of 47%.

Synthesis example G1-3 (step G: solvent=THF)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of tetrahydrofuran, 510.1 mg of oleic acid and 66.2 mg of DMAP were added, and the mixture was cooled to 0°C. Then, 415.4 mg of EDC was added to this solution, and the mixture was stirred at room temperature for 4 hours. Tetrahydrofuran was distilled off under reduced pressure, 10 ml of dichloromethane and 10 ml of 1N hydrochloric acid were added, respectively, and the layers were separated, extracted twice with 10 ml of dichloromethane, and the organic phase was washed with 10 ml of 1% saline. After that, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 509.6 mg of phosphonate compound (9a) with a yield of 66%.

Synthesis example G1-4 (step G: solvent=DMF)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of N,N-dimethylformamide, 510.1 mg of oleic acid and 66.2 mg of DMAP were added, and the mixture was added at 0°C. Cooled to. Then, 415.4 mg of EDC was added to this solution, and the mixture was stirred at room temperature for 2.5 hours. The N,N-dimethylformamide was distilled off under reduced pressure, 10 ml of dichloromethane and 10 ml of 1N hydrochloric acid were added, respectively, and the layers were separated, extracted twice with 10 ml of dichloromethane, and the organic phase was washed with 10 ml of 1% saline. Then, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 603.4 mg of phosphonate compound (9a) with a yield of 78%.

Synthesis example G1-5 (step G: solvent = ethyl acetate)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of ethyl acetate, 510.1 mg of oleic acid and 66.2 mg of DMAP were added, and the mixture was cooled to 0°C. Then, 415.4 mg of EDC was added to this solution, and the mixture was stirred at room temperature for 24 hours. After quenching with 10 ml of 1N hydrochloric acid, the mixture was separated, extracted twice with 10 ml of ethyl acetate, and the organic phase was washed with 10 ml of 1% saline. Then, ethyl acetate was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 568.1 mg of phosphonate compound (9a) at a yield of 73%.

Synthesis example G2-1 (step G: condensing agent=DCC)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of dichloromethane, and 510.1 mg of oleic acid was further added. Then, the solution was cooled to 0° C., 447.2 mg of DCC was added, and the mixture was stirred at room temperature for 23 hours. The obtained white solid was removed by filtration, and the white solid was washed with 3 ml of dichloromethane. Then, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 27.1 mg of phosphonate compound (9a) at a yield of 3.5%.

Synthesis example G2-2 (step G: condensing agent=DCC, additive=DMAP)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of dichloromethane, 510.1 mg of oleic acid and 66.2 mg of 4-DMAP were added, and the mixture was cooled to 0°C. , DCC447.2 mg was added, and the mixture was stirred at room temperature for 2 hours. The white solid obtained was removed by filtration and washed with 15 ml of dichloromethane. Then, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate only) to obtain 458.0 mg of phosphonate compound (9a) at a yield of 59%.

Synthesis example G2-3 (step G: condensing agent=DIC)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of dichloromethane, 510.1 mg of oleic acid was further added, and after cooling to 0° C., DIC339 μl was added and the mixture was cooled to room temperature. And stirred for 3 days. The white solid obtained was removed by filtration and washed with 5 ml of dichloromethane. Then, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate only) to obtain 137.8 mg of phosphonate compound (9a) with a yield of 18%.

Synthesis example G2-4 (step G: condensing agent=DIC, additive=DMAP)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of dichloromethane, 510.1 mg of oleic acid and 66.2 mg of 4-DMAP were added, and the mixture was cooled to 0°C. .. Then, 339 μl of DIC was added to this solution, and the mixture was stirred at room temperature for 24 hours. The white solid obtained was removed by filtration and washed with 5 ml of dichloromethane. Thereafter, the filtrate was concentrated under reduced pressure and purified by silica gel chromatography (ethyl acetate only) to obtain 569.9 mg of a phosphonate compound (9a) with a yield of 73%.

Synthesis example G3-1 (step G: reaction using oleic acid chloride)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

300.0 mg of the cyclic phosphonic acid compound (8a) obtained in Synthesis Example F1-1 was dissolved in 6.0 ml of dichloromethane, 376 μl of triethylamine was further added, and after cooling to 0° C., 717 μl of oleic acid chloride was added, and the mixture was stirred at room temperature. The mixture was stirred for 5.5 hours. After quenching with 10 ml of water, the mixture was extracted twice with 10 ml of dichloromethane, and the organic phase was washed with 1% saline. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 658.4 mg of phosphonate compound (9a) at a yield of 85%.

Synthesis Example G3-2 (Step G: Reaction Using Prepared Oleic Acid Chloride)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

Oleic acid (510.1 mg) was dissolved in toluene (6.0 ml), N,N-dimethylformamide (7 µl) and thionyl chloride (156 µl) were added, and the mixture was stirred at 40°C for 2 hours. Then, toluene was distilled off under reduced pressure. Further, 5 ml of toluene was added, the toluene was distilled off again under reduced pressure, and the residue was dissolved in 3.0 ml of dichloromethane. On the other hand, 300.0 mg of the cyclic phosphonic acid compound (8a) was dissolved in 3.0 ml of dichloromethane, and 376 μl of triethylamine was further added. Stir for hours. After quenching with 10 ml of water, the mixture was extracted twice with 10 ml of dichloromethane, and the organic phase was washed with 1% saline. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 571.2 mg of phosphonate compound (9a) with a yield of 73%.

Synthesis Example G3-3 (Step G: Reaction Using Prepared Oleic Acid Chloride)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

510.1 mg of oleic acid was dissolved in 6.0 ml of toluene, 7 μl of N,N-dimethylformamide and 190 μl of oxalyl dichloride were further added, and the mixture was stirred at 40° C. for 3.5 hours, and toluene was distilled off under reduced pressure. Further, 5 ml of toluene was added, the toluene was distilled off again under reduced pressure, and the residue was dissolved in 3.0 ml of dichloromethane. On the other hand, 300.0 mg of the cyclic phosphonic acid compound (8a) was dissolved in 3.0 ml of dichloromethane, 376 μl of triethylamine was further added, and after cooling with ice, 3.0 ml of dichloromethane of the acid chloride prepared was added dropwise, and the mixture was added at room temperature to Stir for hours. After quenching with 10 ml of water, the mixture was extracted twice with 10 ml of dichloromethane, and the organic phase was washed with 10 ml of water. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 515.6 mg of phosphonate compound (9a) at a yield of 66%.

Synthesis example G4-1 (step G: reaction using p-toluenesulfonic acid chloride)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

Oleic acid (510.1 mg) was dissolved in dichloromethane (3.0 ml), N-methylimidazole (NMM) (430 μl) was further added, and the mixture was cooled to 0° C. and stirred at 0° C. for 1 hour. Thereafter, 3.0 ml of a dichloromethane solution of 300.0 mg of the cyclic phosphonic acid compound (8a) was added dropwise, and the mixture was stirred at 0°C for 1.5 hours. After quenching with 10 ml of water and extraction with 10 ml of dichloromethane twice, the organic phase was washed with 1% saline. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 603.8 mg of phosphonate compound (9a) with a yield of 78%.

Synthesis Example G4-2 (Step G: reaction using Mukaiyama reagent)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

421.9 mg of cyclic phosphonic acid compound (8a) and 717.4 mg of oleic acid were dissolved in 8.5 ml of dichloromethane, and 845 μl of triethylamine and 778.7 mg of 2-chloro-1-methylpyridinium iodide (CMPI) were added and heated for 3 hours. Refluxed. After quenching with 10 ml of water, the mixture was extracted twice with 10 ml of dichloromethane. Dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 263.8 mg of phosphonate compound (9a) with a yield of 34%.

Synthesis example G4-3 (step G: reaction using pyBop)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

200.0 mg of cyclic phosphonic acid compound (8a) and 340.1 mg of oleic acid were dissolved in 4.0 ml of dichloromethane, 420 μl of diisopropylethylamine was further added, and after cooling with ice, 752 mg of pyBop was added and stirred at room temperature for 6 hours. Then, after quenching with 5 ml of 1N hydrochloric acid, the mixture was extracted twice with 10 ml of dichloromethane and 5 ml. The organic phase was washed with 10 ml of water, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 513.8 mg of phosphonate compound (9a) with a yield of 99%. ..

Synthesis Example G4-4 (Step G: Reaction using HATU)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

Cyclic phosphonic acid compound (8a) (300.0 mg) and oleic acid (510.1 mg) were dissolved in dichloromethane (6.0 ml), diisopropylethylamine (630 μl) was further added, and after cooling with ice, HATU824.0 mg was added and the mixture was stirred at room temperature for 24 hours. Then, after quenching with 10 ml of 1N hydrochloric acid, the mixture was extracted twice with 10 ml of dichloromethane. The organic phase was washed with 10 ml of water, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 513.2 mg of the phosphonate compound (9a) with a yield of 68%. ..

Synthesis Example G4-5 (Step G: reaction using HBTU)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

Cyclic phosphonic acid compound (8a) (300.0 mg) and oleic acid (510.1 mg) were dissolved in dichloromethane (6.0 ml), diisopropylethylamine (630 μl) was added, and the mixture was ice-cooled, HBTU822.0 mg was added, and the mixture was stirred at room temperature for 6.5 hr. did. Then, after quenching with 10 ml of 1N hydrochloric acid, the mixture was extracted twice with 10 ml of dichloromethane. The organic phase was washed with 10 ml of water, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to obtain 612.0 mg of phosphonate compound (9a) in a yield of 79%. ..

Synthesis example G4-6 (step G: reaction using COMU)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

Cyclic phosphonic acid compound (8a) (300.0 mg) and oleic acid (510.1 mg) were dissolved in dichloromethane (6.0 ml), diisopropylethylamine (630 μl) was further added, and after ice cooling, COMU928.1 mg was added, and the mixture was stirred at room temperature for 24 hours. Then, after quenching with 10 ml of 1N hydrochloric acid, the mixture was extracted twice with 10 ml of dichloromethane. The organic phase was washed with 10 ml of water, dichloromethane was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate only) to quantitatively obtain 778.2 mg of phosphonate compound (9a).

Synthesis example G5 (telescoping method)
9-octadecenoic acid (9Z)-(2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphospholan-4-yl)methyl ester (9a)

(Process B)
30.0 g of the compound (3a) was dissolved in 456 ml of CH ₂ Cl _2, 42.7 ml of triethylamine was added, and the mixture was cooled to -20°C. MsCl19.1ml was added to this and it stirred at -20 degreeC for 1 hour. The reaction was stopped with 250 ml of water, and after liquid separation, the aqueous layer was extracted with 150 ml of CH ₂ Cl ₂ and the organic layer was washed with 200 ml of water.
(Process C)
The organic layer was concentrated under reduced pressure, the obtained residue was dissolved in 684 ml of methyl ethyl ketone, 1.42 ml of triethylamine and 46.14 g of sodium iodide were added, and the mixture was reacted under heating under reflux for 2.5 hours. After cooling the reaction solution, methyl ethyl ketone was distilled off under reduced pressure, 300 ml of CH ₂ Cl ₂ and 300 ml of water were added, and the layers were separated. The aqueous layer was extracted twice with 150 ml of CH ₂ Cl ₂ , and the organic layer was washed with 300 ml of 2.5% sodium thiosulfate and 0.5% multistory water. Then, the mixture was separated, washed with 300 ml of water, and the organic layer was concentrated under reduced pressure.
(Process D)
The obtained residue was dissolved in DMF (410 ml), cesium carbonate (133.73 g) and dimethyl phosphite (37.64 ml) were added, and the mixture was reacted at 50° C. for 3 hours. DMF in the reaction solution was distilled off under reduced pressure, 300 ml of toluene was added, and the white solid was filtered.
(Process E)
The white solid was washed with 150 ml of toluene, the filtrate was concentrated under reduced pressure, and the obtained residue was dissolved in 410 ml of methanol. Furthermore, 1.95 g of p-toluenesulfonic acid monohydrate was added to this solution, and the mixture was stirred at 20° C. for 2 hours.
(Process F)
The reaction solution was concentrated under reduced pressure, and the obtained residue was dissolved in 821 ml of DMF. DBU (9.21 ml) was added, and the mixture was stirred at 20° C. for 3 hours. Further, the reaction was stopped with 11.71 g of p-toluenesulfonic acid monohydrate, and DMF was distilled off under reduced pressure.
(Process G)
The obtained residue was dissolved in 684 ml of CH ₂ Cl _2, 57.97 g of oleic acid, 7.52 g of DMAP and 47.21 g of EDC were added, and the mixture was reacted at 20° C. for 12 hours. Then, 300 ml of 1N hydrochloric acid was added to separate the layers. The aqueous layer was extracted twice with 300 ml of CH ₂ Cl ₂ , the organic layer was washed with 300 ml of water, and then the organic layer was concentrated. The obtained residue was purified by silica gel chromatography (eluted only with ethyl acetate) to obtain 61.99 g of compound (9a) in 70% (all steps).

[Process (H)]
Example 1 Production of 2 ccPA crystals (good solvent: water, poor solvent: acetone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of Synthesis Example G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 14 hours. .. After the reaction, the reaction solution was concentrated, then dissolved in 5 ml of water at 60°C, and cooled to 20°C. Then, 20 ml of acetone was added dropwise to this solution and aged for 1 hour. The crystals were filtered, washed with 30 ml of acetone and dried under reduced pressure to obtain 651.0 mg of 2ccPA having a purity of 98.874%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.1724 98
9.6675 28
4.9186 21
4.8335 23
4.5164 100
4.1835 14
3.7921 10
IR spectrum (cm ^-1 ): 2920, 2851, 1728, 1204, 1176, 1098, 1012, 774, 744, 721
Melting point: 189°C

Example 2 Production of 2 ccPA crystals (good solvent: methanol, poor solvent: acetone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 13 hours. After the reaction, the reaction solution was concentrated, then dissolved in 2.5 ml of methanol at 40°C and cooled to 10°C. Then, 2.5 ml of acetone was added dropwise to this solution. After the temperature was raised to 20° C., 7.5 ml of acetone was dropped and the mixture was aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 907.6 mg of 2ccPA having a purity of 98.880%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9390 100
9.5838 23
4.9294 22
4.7792 18
4.4982 95
4.1913 19
3.79539
IR spectrum (cm ^-1 ): 2920, 2851, 1733, 1209, 1166, 1097, 1013, 774, 738, 722
Melting point: 188°C

Example 3 Production of 2 ccPA crystals (good solvent: methanol, poor solvent: methyl ethyl ketone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, and 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 13 hours. After the reaction, the reaction solution was concentrated, then dissolved in 2.5 ml of methanol at 40°C and cooled to 10°C. Then, 2.5 ml of methyl ethyl ketone was added dropwise to this solution. After the temperature was raised to 20° C., 7.5 ml of methyl ethyl ketone was dropped and the mixture was aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of methyl ethyl ketone, and dried under reduced pressure to obtain 862.8 mg of 2ccPA having a purity of 98.944%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.8817 92
9.56312 22
4.9186 24
4.7869 20
4.4937 100
4.1835 19
3.7794 9
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1205, 1175, 1099, 1024, 773, 742, 721
Melting point: 187°C

Example 4 Production of 2 ccPA crystals (good solvent: methanol, poor solvent: methyl isobutyl ketone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 12 hours. After the reaction, the reaction solution was concentrated, then dissolved in 2.5 ml of methanol at 40°C and cooled to 10°C. Then, 2.5 ml of methyl isobutyl ketone was added dropwise to this solution. After the temperature was raised to 20° C., 7.5 ml of methyl isobutyl ketone was dropped and the mixture was aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of methyl isobutyl ketone and dried under reduced pressure to obtain 819.1 mg of 2 ccPA having a purity of 99.300%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.8817 100
9.5631 23
4.9294 10
4.7920 10
4.4982 44
4.1874 10
3.80175
IR spectrum (cm ^-1 ): 2920, 2851, 1735, 1210, 1165, 1096, 1012, 776, 738, 722
Melting point: 189°C

Example 5 Production of 2 ccPA crystals (good solvent: methanol, poor solvent: methyl ethyl ketone: acetone = 1:1)
1.0 g of cyclic phosphonate (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 13.5 hours. .. After the reaction, the reaction solution was concentrated, then dissolved in 2.5 ml of methanol at 40°C and cooled to 10°C. Then, 2.5 ml of a mixed solution of acetone and methyl ethyl ketone was added dropwise to this solution. After the temperature was raised to 20° C., 7.5 ml of a mixed solution of acetone and methyl ethyl ketone was dropped, and the mixture was aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of a mixed solution of acetone and methyl ethyl ketone, and dried under reduced pressure to obtain 853.8 mg of 2ccPA having a purity of 98.880%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.8817 100
9.5631 23
4.9186 14
4.7869 13
4.4937 57
4.1874 14
3.7921 7
IR spectrum (cm ^-1 ): 2920, 2851, 1733, 1209, 1166, 1097, 1013, 775, 738, 722

Example 6 Production of 2 ccPA crystals (good solvent: ethanol, crystallization temperature 10° C.)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, and 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 13 hours. After the reaction, the reaction solution was concentrated, then dissolved in 7.5 ml of ethanol at 60°C, cooled to 10°C, and aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 846.6 mg of 2ccPA having a purity of 98.890%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.8248 100
9.5425 24
4.9078 18
4.7920 17
4.4937 78
4.1796 15
3.7762 8
IR spectrum (cm ^-1 ): 2920, 2851, 1728, 1207, 1167, 1097, 1013, 774, 741, 721
Melting point: 189°C

Example 7 Production of 2 ccPA crystals (good solvent: ethanol, crystallization temperature 20° C.)
1.0 g of the cyclic phosphonic acid ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 16 hours. After the reaction, the reaction solution was concentrated, then dissolved in 6 ml of ethanol at 65°C, cooled to 20°C, and aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of acetone and dried under reduced pressure to obtain 783.3 mg of 2ccPA having a purity of 98.997%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.0548 100
9.60446 24
4.9294 7
4.80759
4.5073 29
4.2070 7
3.7857 4
IR spectrum (cm ^-1 ): 2920, 2851, 1728, 1211, 1175, 1096, 1013, 775, 745, 722
Melting point: 190°C

Example 8 Production of 2 ccPA crystals (good solvent: ethanol, poor solvent: acetone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, and 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 13 hours. After the reaction, the reaction solution was concentrated, dissolved in 6 ml of ethanol at 60°C, and cooled to 20°C. Acetone (6 ml) was added dropwise to this solution, followed by aging for 2 hours. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 786.4 mg of 2ccPA having a purity of 99.054%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9967 100
9.60446 24
4.9349 19
4.802 17
4.5073 76
4.1913 13
3.8017 7
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1212, 1172, 1096, 1024, 776, 746, 721
Melting point: 189°C

Example 9 Production of 2 ccPA crystals (good solvent:methanol:ethanol=1:1, poor solvent:acetone)
1.0 g of cyclic phosphonate (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 13.5 hours. .. After the reaction, the reaction solution was concentrated, then dissolved in 2.5 ml of a mixed solution of methanol and ethanol at 60° C., cooled to 10° C., 2.5 ml of acetone was added dropwise, and the temperature was raised to 20° C., 7.5 ml of acetone Was added dropwise and aged for 1 hour. The crystals were filtered, washed with 30 ml of acetone and dried under reduced pressure to obtain 954.2 mg of 2ccPA having a purity of 98.812%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.8817 100
9.56331 24
4.9294 8
4.7920 8
4.498 37
4.1913 10
3.80175
IR spectrum (cm ^-1 ): 2920, 2851, 1734, 1210, 1165, 1097, 1012, 775, 738, 722
Melting point: 189°C

Example 10 Production of 2 ccPA crystals (good solvent: 1-propanol, crystallization temperature 10° C. ) 1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone. 522.3 mg of sodium iodide was added to the mixture, and the mixture was reacted under heating and reflux for 13 hours. After the reaction, the reaction solution was concentrated, then dissolved in 7.5 ml of 1-propanol at 60°C, cooled to 10°C, and aged for 1 hour. Then, the crystals were filtered, washed with 70 ml of acetone, and dried under reduced pressure to obtain 645.0 mg of 2ccPA having a purity of 98.419%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9967 100
9.60446 24
4.90247
4.8075 12
4.5027 32
4.1835 7
3.7636 6
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1207, 1170, 1098, 1014, 774, 745, 721
Melting point: 190°C

Example 11 Production of 2 ccPA crystals (good solvent: 1-propanol, crystallization temperature 20° C. ) 1.0 g of the cyclic phosphonate (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone. 522.3 mg of sodium iodide was added to the mixture, and the mixture was reacted under heating under reflux for 14 hours. After the reaction, the reaction solution was concentrated, then dissolved in 6.0 ml of 1-propanol at 50°C, cooled to 20°C, and aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 866.5 mg of 2 ccPA having a purity of 98.750%.
The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.0548 100
9.6255 24
4.9403 11
4.802 12
4.5073 51
4.1992 11
3.7985 6
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1205, 1174, 1098, 1023, 773, 743, 721
Melting point: 188°C

Example 12 Production of 2 ccPA crystals (good solvent: 1-propanol, poor solvent: acetone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 15.5 hours. .. After the reaction, the reaction solution was concentrated, then dissolved in 6.0 ml of 1-propanol at 60°C, and cooled to 20°C. Acetone (6.0 ml) was added dropwise to this solution, and the mixture was aged at 20° C. for 1 hour. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 866.9 mg of 2ccPA having a purity of 98.902%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.0548 100
9.6255 23
4.9349 9
4.875 10
4.5073 35
4.1952 7
3.7857 4
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1206, 1175, 1097, 1023, 774, 744, 721
Melting point: 187°C

Example 13 Production of 2 ccPA crystals (good solvent: isopropyl alcohol, crystallization temperature 20° C.)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 15 hours. After the reaction, the reaction solution was concentrated, then dissolved in 6.0 ml of 1-propanol at 65°C, cooled to 20°C, and aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 942.2 mg of 2ccPA having a purity of 98.588%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9390 80
9.563 20
4.9186 26
4.797 21
4.4982 100
4.1874 17
3.79539
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1212, 1175, 1095, 1023, 776, 746, 722
Melting point: 188°C

Example 14 Production of 2 ccPA crystals (good solvent: isopropyl alcohol, poor solvent: acetone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, 522.3 mg of sodium iodide was added thereto, and the mixture was reacted under heating under reflux for 14 hours. After the reaction, the reaction solution was concentrated, then dissolved in 6.0 ml of isopropyl alcohol at 60°C, and cooled to 20°C. To this solution, 6.0 ml of acetone was added dropwise, and the mixture was aged at 20° C. for 1 hour. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 915.8 mg of 2ccPA having a purity of 98.761%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.939 86
9.5838 21
4.9132 25
4.7920 21
4.4937 100
4.1874 17
3.7762 8
IR spectrum (cm ^-1 ): 2921, 2851, 1727, 1212, 1175, 1095, 1023, 776, 745, 722
Melting point: 187°C

Example 15 Production of crystals of 2 ccPA (good solvent: 1-butanol, poor solvent: acetone ) 1.0 g of cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone. 522.3 mg of sodium iodide was added, and the mixture was reacted under heating under reflux for 12 hours. After the reaction, the reaction solution was concentrated, then dissolved in 6.0 ml of 1-butanol at 65°C, and cooled to 20°C. To this solution, 6.0 ml of acetone was added dropwise and aged at 20° C. for 3.5 hours. Then, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 598.9 mg of 2ccPA having a purity of 98.773%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9967 100
9.60446 25
4.90248
4.8075 12
4.4982 36
4.1197 7
3.7293 6
IR spectrum (cm ^-1 ): 2920, 2851, 1728, 1206, 1175, 1097, 1013, 774, 745, 721
Melting point: 189°C

Example 16 Production of 2 ccPA crystals (reaction solvent, crystallization solvent: acetone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of acetone, 522.3 mg of sodium iodide was added, and the mixture was reacted under heating under reflux for 48 hours. After cooling to room temperature, the crystals were filtered, washed with 30 ml of acetone and dried under reduced pressure to obtain 898.0 mg of 2ccPA having a purity of 86.921%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.0548 100
9.6255 23
4.9349 27
4.80752
4.5073 99
4.1992 15
3.8145 8
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1211, 1175, 1095, 1023, 776, 746, 722
Melting point: 189°C

Example 17 Production of 2 ccPA crystals (reaction solvent, crystallization solvent: methyl ethyl ketone, poor solvent: acetone)
1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of acetone, 522.3 mg of sodium iodide was added, and the mixture was reacted under heating under reflux for 15 hours. After cooling to room temperature, 11.6 ml of acetone was added dropwise, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 950.7 mg of 2ccPA having a purity of 98.429%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.7684 67
9.5425 16
4.828 27
4.4802 100
4.1757 16
3.7263 10
IR spectrum (cm ^-1 ): 2920, 2851, 1727, 1211, 1175, 1096, 1015, 775, 744, 722
Melting point: 189°C

Example 18 Production of 2 ccPA crystals (reaction solvent, crystallization solvent: methyl isobutyl ketone)
1.0 g of the cyclic phosphonic acid ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of acetone, and 522.3 mg of sodium iodide was added to this, and the mixture was reacted for 6 hours under heating under reflux. After cooling to 10° C. and aging for 1 hour, the crystals were filtered, washed with 30 ml of acetone, and dried under reduced pressure to obtain 950.7 mg of 2ccPA having a purity of 20.777%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9390 100
9.5838 26
4.9132 6
4.802,338
4.4937 23
4.164 16
3.7730 4
IR spectrum (cm ^-1 ): 2921, 2852, 1731, 1208, 1174, 1094, 1011, 778, 745, 722
Melting point: 187°C

Example 19 Production of 2 ccPA crystals (good solvent: methanol, poor solvent: ethyl acetate ) 1.0 g of cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, and iodine was added thereto. 522.3 mg of sodium iodide was added, and the mixture was reacted under heating and reflux for 13 hours. After the reaction, the reaction solution was concentrated, dissolved in 2.5 ml of methanol at 40° C., cooled to 10° C., and 2.5 ml of ethyl acetate was added dropwise. After the temperature was raised to 20° C., 7.5 ml of ethyl acetate was added dropwise and the mixture was aged for 1 hour. Then, the crystals were filtered, washed with 30 ml of ethyl acetate, and dried under reduced pressure to obtain 719.8 mg of 2ccPA having a purity of 98.204%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9390 100
9.5838 22
4.9186 16
4.7920 13
4.4937 62
4.1835 13
3.7921 7
IR spectrum (cm ^-1 ): 2920, 2851, 1728, 1208, 1166, 1097, 1013, 773, 738, 722
Melting point: 190°C

Example 20 Production of 2 ccPA crystals (good solvent: methanol, poor solvent: butyl acetate ) 1.0 g of the cyclic phosphonate ester (9a) obtained by the production method of G5 was dissolved in 11.6 ml of methyl ethyl ketone, and iodine was added thereto. 522.3 mg of sodium iodide was added, and the mixture was reacted under heating and reflux for 13 hours. After the reaction, the reaction solution was concentrated, dissolved in 2.5 ml of methanol at 40° C., cooled to 10° C., and 2.5 ml of butyl acetate was added dropwise. After heating to 20° C., 7.5 ml of butyl acetate was added dropwise, and after aging for 1 hour, the crystals were filtered, washed with 30 ml of butyl acetate, and dried under reduced pressure to obtain 548.0 mg of 2ccPA having a purity of 98.350%. Obtained.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9390 100
9.5838 23
4.9240 9
4.7920 9
4.4982 36
4.1874 9
3.7921 5
IR spectrum (cm ^-1 ): 2920, 2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722
Melting point: 189°C

Example 21 Repurification of 2 ccPA (good solvent: methanol, poor solvent: methyl ethyl ketone)
3.00 g of 2 ccPA obtained in Example 2 was dissolved in 7.3 ml of methanol at 40° C., the solution was cooled to 10° C., stirred for 1 hour, and then 7.3 ml of methyl ethyl ketone was added dropwise. Then, the temperature was raised to 20° C., 22 ml of methyl ethyl ketone was dropped again, and after aging at 20° C. for 1 hour, the crystals were filtered and washed with 36 ml of methyl ethyl ketone to obtain 2.55 g of 2ccPA having a purity of 99.511%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.0548 100
9.6255 24
4.9186 14
4.7920 14
4.498 67
4.1835 14
3.7985 8
IR spectrum (cm ^-1 ): 2920, 2851, 1735, 1210, 1165, 1096, 1012, 776, 738, 722
Melting point: 189°C

Example 22 Repurification of 2ccPA (good solvent: methanol, poor solvent: ethyl acetate)
3.00 g of 2 ccPA obtained in Example 2 was dissolved in 7.3 ml of methanol at 40° C., the solution was cooled to 10° C., stirred for 1 hour, and then 7.3 ml of ethyl acetate was added dropwise. Then, the temperature was raised to 20° C., 22 ml of ethyl acetate was added again, and the mixture was aged at 20° C. for 1 hour. Then, the crystals were filtered and washed with 36 ml of ethyl acetate to obtain 2.52 g of 2ccPA having a purity of 99.610%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.0548 100
9.6255 24
4.9294 17
4.7972 15
4.5073 74
4.1874 15
3.7985 8
IR spectrum (cm ^-1 ): 2920, 2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722
Melting point: 187°C

Example 23 Repurification of 2 ccPA (good solvent: methanol, poor solvent: 1-propanol) 3.00 g of 2 ccPA obtained in Example 2 was dissolved in 7.3 ml of methanol at 40°C, and the solution was cooled to 10°C. After stirring for 1 hour, 7.3 ml of 1-propanol was added dropwise. Then, the temperature was raised to 20° C., 22 ml of 1-propanol was dropped again, and the mixture was aged at 20° C. for 1 hour. Then, the crystal was filtered and washed with 36 ml of 1-propanol to obtain 1.67 g of 2 ccPA having a purity of 99.628%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
16.0548 100
9.6255 24
4.9186 15
4.8075 15
4.498 67
4.1835 13
3.80497
IR spectrum (cm ^-1 ): 2920, 2851, 1734, 1210, 1166, 1097, 1012, 775, 738, 722
Melting point: 187°C

Example 24 Repurification of 2ccPA (good solvent: methanol, poor solvent: methyl acetate)
3.00 g of 2 ccPA obtained in Example 2 was dissolved in 7.3 ml of methanol at 40° C., the solution was cooled to 10° C., and after stirring for 1 hour, 7.3 ml of methyl acetate was added dropwise. Then, the temperature was raised to 20° C., 22 ml of methyl acetate was added again, and the mixture was aged at 20° C. for 1 hour. Then, the crystals were filtered and washed with 36 ml of methyl acetate to obtain 2.49 g of 2ccPA having a purity of 99.559%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9967 100
9.60423
4.9240 11
4.823 10
4.4982 44
4.1874 10
3.7985 5
IR spectrum (cm ^-1 ): 2920, 2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722
Melting point: 189°C

Example 25 Repurification of 2 ccPA (good solvent: methanol, poor solvent: isopropyl acetate) 3.00 g of 2 ccPA obtained in Example 2 was dissolved in 7.3 ml of methanol at 40° C. and the solution was cooled to 10° C. After stirring for an hour, 7.3 ml of isopropyl acetate was added dropwise. Then, the temperature was raised to 20° C., 22 ml of isopropyl acetate was added again, and the mixture was aged at 20° C. for 1 hour. Then, the crystals were filtered and washed with 36 ml of isopropyl acetate to obtain 2.37 g of 2ccPA having a purity of 99.549%.

The X-ray powder diffraction spectrum of the obtained 2 ccPA white crystal was measured and the result was as follows. This X-ray powder diffraction spectrum is an X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å passed through a monochromator.

d (lattice plane spacing) Relative intensity (I/I ₀ )
15.9390 100
9.5838 22
4.9186 10
4.7869 10
4.4937 45
4.1796 10
3.7985 5
IR spectrum (cm ^-1 ): 2920, 2851, 1735, 1210, 1165, 1097, 1012, 776, 738, 722
Melting point: 187°C

Example 26 (2ccPA synthesis: reaction solvent acetone)

200 mg of the cyclic phosphonate compound (9a) was dissolved in 2.3 ml of acetone, and 104.5 mg of sodium iodide was added thereto, and the mixture was reacted for 23 hours under heating under reflux. After cooling to 20°C, the resulting white solid was filtered. After the crystals were washed with acetone, 174.2 mg (melting point 189.6° C.) of white crystals of 2ccPA(1) were obtained.
¹ H-NMR (500 MHz, CDCl ₃ )
δ: 0.79 (t, J=6.5 Hz), 1.19-1.23 (m, 20H), 1.36 (m, 1H), 1.51 (br, 2H), 1.79 ( m, 1H), 1.93 (br, 4H), 2.26 (t, J=7.5 Hz, 2H), 2.72 (m, 1H), 3.65-4.10 (m, 4H). , 5.20-5.28 (m, 2H)

[Synthesis study according to literature prescription]
Comparative Example 1: Synthesis of phosphonic acid dimethyl ester, Arbuzob reaction

15.00 g of the iodine compound (5a) was dissolved in 105 ml of trimethyl phosphite, and the mixture was heated under reflux for 14 hours. Then, 210 ml of trimethyl phosphite was added again, and the mixture was heated under reflux for 6 hours. After concentration, the obtained residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 8.34 g of dimethyl phosphonate compound (6a) in a yield of 60%, but a by-product of unknown structure Was mixed.

Comparative Example 2: (2-methoxy-2-oxo-2λ ⁵ Synthesis of [[1,2]oxaphosphoran-4-yl)methanol, cyclization reaction

8.34 g of the dimethyl phosphonate compound (6a) obtained in Comparative Example 1 was dissolved in 417 ml of toluene and 14.1 ml of methanol, 1.53 g of p-toluenesulfonic acid monohydrate was added, and the mixture was heated under reflux for 3 hours. did. Toluene and methanol were distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=15:1) to obtain 2.44 g of the cyclic phosphonic acid compound (8a) in a yield of 42%.

Comparative Example 3: (9-octadecenoic acid-2-methoxy-2-oxo-2λ) ⁵ Synthesis and condensation reaction of -[1,2]oxaphosphoran-4-yl)methyl ester

2.42 g of the cyclic phosphonic acid compound (8a) obtained in Comparative Example 2, 4.11 g of oleic acid, and 534.0 mg of 4-dimethylaminopyridine were dissolved in 48.6 ml of dichloromethane. After cooling this with ice, 3.35 g of EDC, 1.23 g of oleic acid, 2.23 g of EDC, and 808 ml of dichloromethane were added, and the mixture was stirred at room temperature for 24 hours. After diluting with 571 ml of methanol, 300 ml of water was added. After separation, the aqueous phase was extracted twice with 300 ml and 100 ml of ethyl acetate, the organic phase was dried over magnesium sulfate, and then ethyl acetate and methanol were distilled off under reduced pressure. The obtained residue was subjected to silica gel chromatography (ethyl acetate). Only) to obtain 2.65 g of a cyclic phosphonate compound (9a) with a yield of 42%.

Comparative Example 4: (9-octadecenoic acid-2-methoxy-2-oxo-2λ) ⁵ -[1,2]oxaphosphoran-4-yl)methyl ester proton type synthesis, demethylation reaction

2.51 g of cyclic phosphonate compound (9a) synthesized in Comparative Example 3 was dissolved in 303 ml of dichloromethane, cooled to -15°C, 2.31 ml of bromotrimethylsilane was added, and the mixture was stirred at -15°C for 4.5 hours. did. The reaction solution was poured into 200 ml of ice water, extracted with 750 ml of diethyl ether, separated, and again extracted with 200 ml of diethyl ether twice. The organic phase was dried over sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (chloroform:methanol=5:1) to obtain 367.6 mg of a compound (proton type of 10a:2ccPA) in a yield of 15 Obtained in %.

Comparative Example 5: (9-octadecenoic acid-2-methoxy-2-oxo-2λ ⁵ Synthesis of -[1,2]oxaphosphoran-4-yl)methyl ester sodium salt

418.6 mg of the compound (10a) obtained in Comparative Example 4 was dissolved in 30 ml of diethyl ether, 20 ml of a 0.05 M aqueous sodium hydroxide solution was added, and the mixture was stirred and then separated. By freeze-drying the aqueous phase, 250.8 mg of 2ccPA(1) was obtained with a yield of 57% (purity 67.934%).

Test Example 1: 35° C. Stability Test 2 ccPA crystals obtained in Example 3 (invention), 2 ccPA obtained in Comparative Example 5 (reference formulation) and 2 ccPA amorphous were stored at 35° C. for 1 month, respectively. The stability test was carried out. The results are shown in Table 1 below.

As the amorphous of 2 ccPA, 300 mg of 2 ccPA obtained in Example 3 was dissolved in 5 ml of water and freeze-dried.

The stability test was carried out by weighing about 15 mg each of the crystals of 2 ccPA of the present invention, the literature formulation and amorphous of 2 ccPA, diluting with 5 ml of acetonitrile/water (1/1), and diluting 5 μl of the diluted solution every 1 week by Shimadzu Corporation. It was analyzed by LC-2010 CHT.

As shown in the results of Table 1 above, 2 ccPA produced by the literature formulations of Comparative Examples 1 to 5 had poor purity and was unstable, and the amorphous form of 2 ccPA had good purity, but decomposition proceeded every week, and It was stable.

On the other hand, the crystals of 2ccPA obtained by the production method of the present invention were highly pure and stable. Even after 56 days, the purity of 99.493% was maintained, and the storage stability was superior to that of 2ccPA obtained by the conventional production method.

Claims (8)

Formula (1)

A crystal of cyclic phosphonic acid sodium salt (2 ccPA) represented by: The crystal according to claim 1, which has a characteristic peak at a position of 15° to 17° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum. The crystal according to claim 1, which has a characteristic peak at a position of 9° to 10° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum. The crystal according to any one of claims 1 to 3, which has a characteristic peak at a position of 3° to 5° as a diffraction angle represented by 2θ in an X-ray powder diffraction spectrum. The crystal according to claim 1, which has a maximum intensity at d (lattice plane interval) of 15.7684 to 16.1724 in an X-ray powder diffraction spectrum obtained by copper radiation of λ=1.54059Å through a monochromator. The X-ray powder diffraction spectrum obtained with copper radiation of λ=1.54059Å through a monochromator, having a characteristic peak at d (lattice plane spacing) of 15.7684 to 16.1724. crystal. The crystal according to claim 1, which has a peak at d (lattice plane interval) below in an X-ray powder diffraction spectrum obtained by copper radiation of λ=1.54059Å through a monochromator.
d (lattice spacing)
15.7684 to 16.1724
9.5425-9.6675
4.9024 to 4.9403
4.7869-4.8335
4.4802-4.5164
4.1641 to 4.2070
3.7263 to 3.8145 In the X-ray powder diffraction spectrum obtained by the copper radiation of λ=1.54059Å through a monochromator, d (lattice plane spacing) satisfies any of the following requirements (a) to (y): The crystal according to.
(A) d (lattice plane spacing)
16.1724
9.6675
4.9186
4.8335
4.5164
4.1835
3.7921

(B) d (lattice spacing)
15.9390
9.5838
4.9294
4.7972
4.4982
4.1913
3.7953

(C) d (lattice plane spacing)
15.8817
9.5631
4.9186
4.7869
4.4937
4.1835
3.7794

(D) d (lattice spacing)
15.8817
9.5631
4.9294
4.7920
4.4982
4.1874
3.8017

(E) d (lattice plane spacing)
15.8817
9.5631
4.9186
4.7869
4.4937
4.1874
3.7921

(F) d (lattice plane spacing)
15.8248
9.5425
4.9078
4.7920
4.4937
4.1796
3.7762

(G) d (lattice spacing)
16.0548
9.6046
4.9294
4.8075
4.5073
4.2070
3.7857

(H) d (lattice plane spacing)
15.9967
9.6046
4.9349
4.8023
4.5073
4.1913
3.8017

(I) d (lattice plane spacing)
15.8817
9.5631
4.9294
4.7920
4.4982
4.1913
3.8017

(J) d (lattice plane spacing)
15.9967
9.6046
4.9024
4.8075
4.5027
4.1835
3.7636

(K) d (lattice spacing)
16.0548
9.6255
4.9403
4.8023
4.5073
4.1992
3.7985

(L) d (grating plane spacing)
16.0548
9.6255
4.9349
4.8075
4.5073
4.1952
3.7857

(M) d (lattice spacing)
15.9390
9.5631
4.9186
4.7972
4.4982
4.1874
3.7953

(N) d (lattice plane spacing)
15.939
9.5838
4.9132
4.7920
4.4937
4.1874
3.7762

(O) d (lattice plane spacing)
15.9967
9.6046
4.9024
4.8075
4.4982
4.1719
3.7293

(P) d (lattice spacing)
16.0548
9.6255
4.9349
4.8075
4.5073
4.1992
3.8145

(Q) d (lattice plane spacing)
15.7684
9.5425
4.828
4.4802
4.1757
3.7263

(R) d (lattice plane spacing)
15.9390
9.5838
4.9132
4.8023
4.4937
4.1641
3.7730

(S) d (lattice plane spacing)
15.9390
9.5838
4.9186
4.7920
4.4937
4.1835
3.7921

(T) d (lattice plane spacing)
15.9390
9.5838
4.9240
4.7920
4.4982
4.1874
3.7921

(U) d (lattice spacing)
16.0548
9.6255
4.9186
4.7920
4.4982
4.1835
3.7985

(V) d (lattice plane spacing)
16.0548
9.6255
4.9294
4.7972
4.5073
4.1874
3.7985

(W) d (grating spacing)
16.0548
9.6255
4.9186
4.8075
4.4982
4.1835
3.8049

(X) d (lattice plane spacing)
15.9967
9.6046
4.9240
4.8023
4.4982
4.1874
3.7985

(Y) d (lattice plane spacing)
15.9390
9.5838
4.9186
4.7869
4.4937
4.1796
3.7985

Images